6-halogeno-1, 4, 6-pregnatrienes and the 1, 2-dihydro analogs thereof



United States Patent 3,264,332 j 6-HALOGENO-1,4,6-PREGNATRIENES AND THE 1,2-DIHYDRO ANALOGS THEREOF David H. Gould, Leonia, and Elliot L. Shapiro, lrvington, N .J., assignors to Scheriug Corporation, Bloomfield,

N.J., a corporation of New Jersey No Drawing. Filed Jan. 7, 1959, Ser. No. 785,326 21 Claims. (Cl. 2 60-39145) thereof which are more specific in their'anti-inflarnmatory action than previously known anti-infiannnatory drugs.

The new compounds of our invention are compounds of the group represented by the following formula:

wherein X is a member of the group consisting of H, and halogen of atomic weightless than 126; Y is a member of the group consisting of O and (H, BOH); Z is a halogen of atomic weight less than 126; R is a member of the group consisting of H and lower alkanoyl; and A is a member of the group consisting of H and lower alkyl; and the 1,2-dihydro analogs thereof.

The alkyl group at the 16-carbon may be in an or or fl-position, and may be straight chained or branched and contains preferably from 1 to 4 carbon atoms. Within this group are substituents such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.

Illustrative of the 21-esters contemplated above are of cortical activities with a concurrent enhancement of the anti-inflammatory property. We have discovered that these 6-halogenated 6-unsaturated corticoids have physiological properties which have been drastically and unexpectedly modified from the parent 6-dehydrocorticoids.

6-dehydroprednisone acetate is known to be an active anti-arthritic corticosteroid similar to cortisone, both of which cause thymus involution in animals and in both animals and humans cause eosinopenia and liver glycogen deposition as well as a reductiton in inflammation. On the other hand, 6-'bromo-6-dehydroprednisone acetate of our invention is devoid of activities other than anti-inflammatory, and thus is valuable in not causing extraneous physiological effects so that full benefit may be derived from the anti-inflammatory activity.

In like manner, the 6-halogeno-4,6-pregnadienes of the above formula are more specific in anti-inflammatory activity than their non-fi-halogenated analogs by concomitantly being devoid of extraneous undesirable effects. For example, 6-dehydrocortisone 21-acetate (4,6-pregnadiene- 17a,21-(llOl-3,11,20-l2l'i01'l6 2l-acetate) is a very weak anti-inflammatory agent as determined in the well known granuloma pouch test, and is considered inactive as an anti-arthritic agent in man. 6-br-omo-6-dehydrocortisone acetate, on the other hand, when measured by the granulcma pouch test not only exhibits a specificity of action in exhibiting anti-inflammatory activity alone but also possesses this therapeutic activity in a much greater and effective degree than the non-halogenated analog, having an anti-inflammatory potency of the order of prednisone acetate.

The increase in the anti-inflammatory action of the 6- halogenated-4,6-pregnadienes over that of their non-halogenated counterparts is surprising in view of recent clinical findings (Oliveto et al., I DC. 22, 1720 (1957)) which indicate that in the 1,4-pregnadiene series, the metabolic efiects in man are considerably diminished by the substitution of a halogen atom for a hydrogen atom at C-4.

While both the 6-halogeno-dienes and trienes of Formu- 1a I possess the therapeutic activity described herein, the 6-h-alogeno dienes have further value as intermediates in the preparation of the pregnatrienes of our invention.

The halogeno-pregnadienes IA are prepared by any of the three general procedures outlined below wherein A, X, Y, Z and R have the same meanings given above, Z is a halogen and Z" is a halogen of atomic weight less than 36. For purposes of simplicity only the A and 'B ring structures are drawn whenever the remaining portion of the steroid molecule is unchanged in the designated reaction. The dotted line between the 1 and 2 carbon atoms is to indicate that these procedures are also applicable to the l-dehydro analogs of the indicated compounds.

and the 6-chloro-7-brom0-4-pregnenes. -genationmay also be accomplished by adding to the..4,6-

The 4,6-pregnadienetstarting compounds II may .be

prepared directly from the corresponding 4-pregnene 21iacetate by dehydrogenation with an agent such as chloranil in refluxing xylene, orby halogenating 4-pregnene 21(- ace.-

tates with agents such as N-bromosuccinimide, N-chlorosuccinimide,and the like, followed by subsequent dehy.- drohalogenation in refluxing ,collidine or lutidine. Thus,

for example, treatmentof cortisone 21-acetate with Nibromosuccinimide yields" 6-bromocortisone ZI-acetate which is dehydrobrominated in refluxing lutidine to yield 6-dehydrocortisone.

In like manner, .4,6-pregnadienes II, wherein A is a lower alkylgroup, are obtained from the corresponding 16-a1kyl-4-pregnene 21-acetateswhich are, prepared as dei-- scribed. by Rausser et al., in their copending application- Serial No. 733,843, filed May 8, 1958, now Pat. No

The dihalogenated intermediates, III, wherein Z andZ' are identical are obtained from the corresponding 4,6.-

pregnadienes a series of halogenating reagents under proper conditions. For example, hydrogen fluoride .in methylene chloride in admixture with 6-dehydrocortisone 21-acet-ate. followed by addition of N-bromoacetamide in,

methylene. chloride yields 6-flu'oro-7-bromo-4-pregnene 21- acetate. Dehydrohalogenation of the 6,7-dihalo'geno-4- pregnenes'III yields the novel 6-halogeuo-4,6-dienes IV by treatment with a base such as collidine, lutidiue, dimethylformamide or diethy-lformamide, with or Without the presence of calcium or sodium carbonate for neutralizing the released acid.

An alternative synthesis of compound IV from'II is through the 6ot-7a-epoxi-de, V, which is prepared from H by means of a per-acid such as perbenzoic or perphthalic acid. The epoxide V is then converted to the 6-halogeno-. 7-hydroxy VI through the use of a hydrohalic acid. By

dehydrating intermediate VI with such reagents as acetic acid, perchloric acid, for the like, the novel compounds IV are obtained.

In the above procedures, is ispreferable, generally, to

protect any primary or secondary-hydroxyl- -group which may be present, such as atthe ll-nor- 2l-position. This may be accomplished byesterifying :the t-hydroxyl groups in the usuallmanneror by preservation of thehydroxy in theyform of the .9/3,11/3-epoxide.

acid or alkali or microbiologically according to procedures described in South African Patent No. 3462/55.

A third route whereby thertherapeutical-ly valuable 6-,

halogeno-4,6pregnadienes of "FormulaIAare obtained a utilizes as starting compounds 6-halogeno-4-pregnenes of Formula VIIlwhich,1upon bromination with agents such as bromine, N-bromosuccinimide, or. N-bromoacetamide,

yields 6-bromo-6-halo'geno-4-pregnene intermediates VIH.

Subsequent dehydrohalogenation by means of a base such as .lutidin'e or dimethyl formarnid'e converts VIII to a 6- halogeno-4,6-pregnadiene of Formula IA.

Some starting compounds of Formula VII are known,

such as the,6-fluoro-9a-halogeno-4-pregnenes and their ldehydro analogs.

Other 6-halogeno-4-pregnenes of Formula VII: may be preparedfrom the corresponding 3-keto-4-pregnene by epoxidizing 3-ethylenei 'ketal derivative'of a 4-pr egnene with a per-acid such as peracetic, perbenzoic and the like to form'the B-ethylene ketal-5a,6a-epoxypregnene inter:- mediate. Upon the addition of a hydrohalic acid such as, for example, hydrochloric to the: Saba-epoxy, there is obtained the 6-chloro-3-keto-4-pregnene, of :the starting compound VH1 L The halogenopregnatrienes falling under Formula I are prepared preferably from their. 6-halogeno-4,6,-pregnadi-.

ene analogs, This'conversion is effected microbiologically by employing, .fo'r example,.microorg-anisms such as- Corynebacterium simplex (A.T.C';C. 6946) as described in U.S.'Patent No. 2,837,464. Thedehydrogenation of:

the A-ring whereby the. A -bond is inserted can also be ac.- complished byknown chemical'methods such as reacting The A -6-ha1ogeno esters IVthus formed may; be saponifiied to the free alco- I hols ofFormula- IAeither chemically by the use of dilute of sequences of reactions similar to those whereby the 6- halogeno-4,6-pregnadienes are prepared. Thus, for example, 6-dehydroprednis0ne acetate is brominated to give 6,7-dibrornoprednisone 2l-acetate intermediate which, on treatment with a base such as lutidine yields 6-bromo- 1,4,6-pregnatriene 21-acetate of our invention.

The 1,4,6-pregnat-riene starting compounds, the l-dehydro analogs of II, may be prepared directly from the corresponding known 1,4-pregnadiene 21-acetates by dehydrogenation with an agent such as chloranil in refluxing xylene; or by the allylic halogenation of a 3-keto-1,4- pregnadiene 21-acetate with agents such as N-bromosuccinimide, N-chlorosuccinimide to form the corresponding 3-keto-6-halogeno-1,4-pregn-adiene which is subsequently dehydrohalogenated to refluxing col-lidine or lutidine.

1,4-pregnadiene compounds containing a 16-alkyl substituent may be prepared as described by Rausser et al.,- supra. The 16-alkylated-1,4-pregnadienes are then converted to the l6-alkyl-1,4,6-pregnatrienes and thence to the 6-halogeno-pregnatrienes by processes analogous to those indicated above.

When our 6-halogeno-1,4,6-pregnatrienes are prepared according to the third procedure described heretofore, the

necessary 6-halogeno-1,4-pregnadiene starting compounds VII may be prepared by epoxidizing a corresponding 1,5- pregnadiene to form a 5oz,6a-epoxy-1-pregnene intermediate which, upon the addition of a hydrohalie acid, yields the necessary .6-halogeno-1,4-pregnadiene. Thus, 1,5- pregnadiene-17a,21-diol-3,11,20-trione 2l-acetate is reacted with peracetic acid to give 5a,6u-oxido-1-pregnene- 17a,21diol-3,l1,20-trione 2l-acetate which, upon the addition of hydrogen chloride, yields the desired starting compound fiwchloroprednisone 21-acetate.

The 1,5-pregnadienes and their 1-6-alkyl analogs (necessary intermediates tor the preparation of the 6-halogeno- 1,4-pregnadiene intermediates VI'I) are described by Nussbaum et al. in copending applications Serial No. 725,521, filed April 1, 1958, now abandoned, and Serial No. 770,- 315, tiled October 29, 1958, now U.S. Patent No. 3,013,- 033, respectively. Intermediates of Formula VII containing a 6-fluoro substituent may also be prepared as described in copending application of Nussbaum et al. Serial No. 770,288 filed October '29, 1958.'

In one preferred method, the 9a-balogen atom, and prefenably the 9a-fluorine atom is introduced into the 6- l1a1ogeno-6-del1ydro-4-monoene and 1,4-diene 21-esters as represented, for example, by 6-fluoro-6-dehydrohydrocortisone acetate and 6-fluoro-6-dehydroprednisone acetate, respectively, by first dehydrating 6-fiuoro-6-dehydroprednisolone acetate, for example, with an alkyl or arylsulfonyl chloride, e.g. methanesulfonyl chloride, in an organic medium such as pyridine to effect the production of the corresponding M -derivative, i.e. 6-fluoro-1,4,6,9- (11) p-regnatetraene-17a,21 dio1-3,20-dione 21-acetate and, in the case of the monoene, 6fluoro-4,6,9,(11)- pregnatriene-17a,\21-diol-3,20-dione 21 acetate. Placement of a halogen and preferably bromine rat the 9u-carbon position is accomplished by conventional means such as, for example, by reacting the M -steroid with hypobromous acid which is preferably prepared in situ by the reaction of combinations such as N-bromoacet-amide and perchloric acid yielding directly the corresponding 6- fluoro-9a-bromo-6 dehydroprednisolone 21-aceta-te, and 6- fiuoro-9a-bromo-6-del1ydrohydroeortisone 21-acetate.

An alternative method of introducing a 9u-halogen atom into the 6afiuoro-4,6-pregnadienes and 1,4,6-pregnatrienes of Formula I utilizes as starting compounds the 9a-bromohydrins prepared as above which can be refluxed with mild alkali, such as sodium acetate in methanol to form the corresponding 95,11B-oxido derivatives, such as 95,1118-oxido-G-fluoro-6dehydroprednisolone 21-acetate or 9,8,1lB-oxido-6-fluoro-6-dehydrohydrocortisone 21-acetate. These latter compounds are then reacted with hydrogen fluoride in chloroform with or without ethanol and/or tetrahydroturan to cause the formation of 6,90- difluoro-6-dehydroprednisolone acetate and 6,9a-difluoro- 6-dehydrohydrocortisone'ZI-acetate. Similarly, the substitution of anhydrous hydrogen chloride for hydrogen fluoride in this reaction results in the production of the corresponding 9a-chloro derivatives.

The 9a-lhalogeno-11fl-hydroxy compounds of Formula I thus prepared are readily converted by oxidation to the corresponding ketones by known means such as, tor example, with chromium trioxide in pyridine. These compounds are readily hydrolyzed .at the C21 position by micro-bio logical procedures with microorganisms such as Flavobacteriwm dehydrogenans or by using standard hydrolytic agents such as aqueous methanolic potassium bicarbonate, sodium carbonate, concentrate-d hydrochloric in methanolchloroform, perohloric acid in methanol or like substances as disclosed herein to prepare the corresponding 21-alcohols.

Our therapeutically valuable 6-halogeno-4,6-pregnadienes and 6-halogeno-1,4,6-pregnatrienes are preferably administered orally in the form of tablets containing for example about 5 to 25 mg. per tablet with a solid carrier containing one or more of the usual excipients such as starch, sugar, gums, soaps, clays and the like. Where I parenteral administration is indicated, subcutaneous or intramuscular injection of the substance dissolved or suspended in a suitable non-toxic liquid vehicle is preferred. Parenteral compositions preferably contain a 2'1-ester of the 6-halo-4,6-pregnadiene or the l-dehydro analog thereof. In the treatment of skin conditions such as atopic dermatoses, topical preparations such as ointments or creams containing 0.15% of active ingredient is advantageously employed. In some instances, microcystalline suspensions are injected intra-articularly. These microcrystalline suspensions are adaptable to nasal sprays as well.

The compounds of our invention which are preferentially utilized as indicated above are 6 fluoro analogs of 6- dehydroprednisone, 6-dehydroprednisolone, 6-dehydrocortisone, -6-dehydrohydrocortisone, and particularly the 90cfluoro-ld-methyl-(a and B)-analog-s and their 21-esters.

The following examples are illustrative of the procedures employed in preparing the compounds of this invention but are not to be construed as limiting the scope thereof; the scope of our invention being limited only by the appended claims.

EXAMPLE 1 6-br0m0-6-dehydr0c0rtis0ne 21-acetate The requisite intermediate, 6,7-di-bromo-cortisone 21- acet-ate, is prepared from 6-dehydrocortisone 21-acetate in the following manner. Four grams of 6-dehydrocortisone acetate are dissolved in ml. of methylene chloride under .argon gas and 1.7 g. of bromine in 3 ml. of methylene chloride is added. The solution decolorizes rapidly and is poured into water after two minutes, extracted with methylene chloride, then washed to neutrality with water. The solution is dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Hexane is added to the residue and the mixture then reevaporated to give a solid residue of 6,7-dibromocortisone 21-acetate.

To the dibromide prepared above there is .added, under argon gas, 60 ml. of 2,4-lutid-ine. The mixture is refluxed 20' minutes, cooled, then poured into an excess of dilute sulfuric acid, and the acidic mixture extracted with methylene chloride. The organic solution is washed with water, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue is crystallized from acetone-hexane to yield 6-bromo-6-debydroborti soi1e 2l-acetate, M.P. 244 C. e

EMMPLE 2 6-bromo-d-dehydrocortisone Two grams of fi-abromo-d-dehydrocortisone 2l-acetate prepared as in Example v1, are dissolved in 70 ml. of 1:2 1 chloroform-methanol and chilled to 15 C. while argon is I bubbledslowly through the solution, and 3.5 ml.'of.an

aqueous 4% solution of sodium hydroxide is then added rapidly with cooling. The mixture is stirred 3 minutes, acidified with 0.4 cc. of acetic acid, then stirred .10 minutes longer. The resulting solution isconcentrated to 30 ml, diluted with water and extracted with chloroform. The organic solution is washed to neutrality with Water,

dried over magnesium sulfate, filtered and evaporated.

The resulting residue is crystallized from acetone to give 6-bromo-6-dehydrocortisone. A max.=298 m, (CH OH).

EXAMPLE 3 6-brom0-6-dehydr0hydrocorrisane' 21'-acetate The requisite. intermediate, -6,7-dibromohydrocortisone,

ZI-acetate is prepared from'5 g. of 6-dehydrohydrocortisone Z'I-acetate and-2.25- g. of bromine'in the manner der scribed in Example 1. r

To the resulting dibromide is added 100 ml. of dimetl1-- ylformamide and the mixture is refluxed 30 minutes. The

solution is evaporated in vacuo to a solid residue which is crystallized from acetone toyield fi bromo-fi-dehydrohydrocortisone 2l-acetate,

xiii? 2.90, 5.66, 516,6.02, 6.20, 6.50, 8.12,, EXAMPLE 4 6-brom0-6-dehydr0hydroc0rtisone The 6-bromohydrocortisone of Example 3 (1 g.) is 'saponified as described in Example 2 with 1.75 ml. of 4% aqueous sodium hydroxide. The crude product iscrystali lized from aqueous acetone, to yield 6-bromo-6-dehydrohydrocortisone -2.l-acetate,

Aggie 2.89, 294,6.04, 619,.

EXAMPLE 5 6-chl0r0-6-dehydr0cortis0ne 21 -acetate The requisite intermediate, .6,7dichlorocortisone 21- acetate, is4prepared from 2 g. of 6-dehydrocortisone 2-1- acetate and 0.38 gram of chlorine in methylene chloride in the manner described in Example l.

The dichloride prepared above is dissolved in 50' ml; of 2,4,6-collidine and heated for 3 .hours at 90-95 C. The reaction mixture is purified, and. the product isolated in the manner of Example 1 to give 6-chloro-6-dehydrocortisone 21-acetate which is crystallized from acetonehexane,

A2552 295 m EXAMPLE 6 6-chl0r0-6-dehydr0c0rtisone The 6-chloro--dehydrocortisone ZI-acetate' prepared in Example 5 is saponified in the manner of Example; 2 to yield -6-chloro-6-dehydrocortisone.

EXAMPLE 7 6-flu0ro-6-dehydrocortisone ZI-acetat The requisite intermediate, 6-fluoro-7-bromocortisone ZI-acetate, is prepared in the following manner; Methylene chloride ml.) saturated with hydrogen fluoride; is added dropwise at room temperature to a stirred solution of 6-dehydrocortisone Zl-acetate (1 g.) and -N-' bromoacetamide (0.395 g.) in freshly distilled methylene chloride (20 ml.). After the addition is completed, thei reaction mixture is stirred for twohours at room temperature. The solution .is then diluted with an additional 500 ml. of methylene chloride,.washed with water until neutral, dried over magnesiumsulfate, filtered, and evap- 'orated to dryness, in vacuo yielding a residue of d-tfluorosulfate, filtered, and evaporated in .vacuo to,

.7 bromocortisone ,-21-acetate.. .-This is used .without further purification in the following procedure;

. The.6-fluoro-7 bromoc0rtisone 2f1-acetate,:-is reacted: With; 2,4-lutidine; under .argon gas, in the mannermof Example. 1. The isolated icrude product. is chromato-= graphed on activated magnesium silicate. Theffractions eluted withf5075% 'ether inehexane; :are combined and:

crystallized from acetone-hexaneto give .6-fluoro-6-de} hydrocortisone 21-acetate,7tmax..=297 mp. (CH OH). I

EXAMPLE 8 i 6 12mm0-o-dehydrohydrocortisonei.11,21 -diacetate' A. G-DEHYDROHYDRO'CORTISONE 1].,2 1%DIACETA TE.

The requisite intermediate; 6abromohydrocortison e.

ILZI-diacetate, is preparedfrom: hydrocortisone ';-l 1,21-

diacetate (89 g.) in one'liter ofichlorobenzenefand one.

literof carbon-tetrachloride to which'is added 3.7 g. of freshly crystallized 'N bromosuccin'imide under an at, moshere of nitrogen. Therefluxing solution is illuminated with an.-incande'scent lamp,(RFL'NIJ. 2) until'the reaction solution is negative to starchiodide paper. Thesolution is then chilled, washed withtvvater; dried over;

magnesium sulfate, filteredfland concentrated in vacuo. The resulting residue is substantially o bromohydrocortisone 11,21-dia'cetate. 3

Without further purification, the fi bromohydrocortisone ,1l,2-1-diacetate prepared above. isi dissolved in 200 j ml. of 2,4-lutidine and refluxed for two hours. The solution-is then chilled,'-poured into ice and water containing enough sulfuriciacidto neutralize hte excess lutidine, and

extractedwith methylene chloride. The organic layer-is Washed with water,- dried over-magnesium sulfate, filtered, and concentrated in. vacuo.

eluates yields 6-'dehydrohydrocortisonea. 'l'l',2;l-"cliacetatc,- Amax.=28i1' (MeOHi)l. I

B. G-BROMO-G-DEHYDROHYDROCORTISONE '11,'21.-DIACETATEJ V The requisite intermediate 6,7-dibromohy locortisone 11,2-1-diacetate is prepared as follows. To 2.2 g; of above prepared 6-dehydrohydrocortisone 11,-2.1-diacetate .dis- I solved in ml. of methylene chloride under argon, there a is added a drop of hydrogen bromide in acetic acidfollowed by the d-ropwise addition'of 0.85 g. of bromine. in 3 ml. of'methylene chloride within 45; minutes; atroo'm temperature. The reaction-solution is? then poured into water, andextractedwith methylene: chloride; The or ganic layer islwashed with water, dried over magnesium yield 6,7-di bromohydrocortisone ,ILZl-diacetate. Withoutafurther purification the .dib'romidediacetate prepared immediately above is dissolved in, 2,4-lutidine (60 ml.) and refluxed'for 30"rninutes. The reaction mix.

ture is cooled, poured into dilute acid sufficient to neutralize any excess lutidine, and extracted-With methylene chloride. The organic solution is washedwith Water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue .is crystallizedv from; acetone-hexane to give 6-bromo+6-dehydrohydrocortisone 11,21-diacetate, Amax.=298 m (CH OH).-.

EXAMPLE .9 I 6-bromo-9u fluoro-6-dehydrohydrocortisone The resulting residue-is chromatographedover magnesium silicate. Elution. with 40% to.:80% ether-in-hexane, andjconcentration of they 9 EXAMPLE 6-brom0-6-dehydrocortis0he 21 -n-butyrate A. G-DEHYDROCORTISONE 21-BUTYRATE In the manner of Example 8A, cortisone 21-butyrate is reacted with N-bromosuccinimide toform the necessary intermediate, 6-bromocortisone 2l butyrate, which in turn, is reacted with 2,4-lutidine to give 6-dehydrocortisone 21- :butyrate.

B. G-BROMO-G-DEHYDROCORTISONE 21-BUTYRATE 6-dehydrocortisone Zlfloutyrate /('2 g.), prepared in Example 10A, is reacted with bromine (0.83 g.) in the manner of Example 813 to yield 6,7-dibron1ocortisone 21- butyrate.

Without further purification, the dibromo-Zl-butyrate prepared above is reacted with 60 ml. of 2,4-lutidine in the manner of Example 8 B to yield 6-bromo 6-dehydrocortisone ZI-butyrate which, is recrystallized from acetonehexane, )rmax.=298 m (CH OI-I).

EXAMPLE 11 6-chl0r0-9ot-br0m0-6-dehydr0hydrocortisone The requisite intermediate, 6-br-omo-9,8,11B-epoxy-17u, 21-dihydroxy-4-pregnene-3,20-dione 21-acetate, is pre: pared in the manner of Example 8A from 95,11B-epoxy- 1711,21 dihydroxy-4-pregnene-3,20-dione 21-acetate and N-bromosuccinimide.

The crude 6-bromo-9B,11,B-epoxy intermediate thus prepared is dissolved in 200 ml. of 2,4-lutidine and reacted in the manner of Example 8A to give 9p,11;8-epoxy- 1711,21-dihydroxy-4,6-pregnadiene-3,20-dione 21-acetate.

PREGNADIENE-3,20-DIONE 21-ACETATE 95,11/3-epoxy-4,6-pregnadiene (2g) prepared in Example 11A is dissolved in methylene chloride and added to a solution of 0.87 g. of iodine monochloride in methylene chloride under argon. After the solution is completely decolorized it is poured into water and extracted with methylene chloride. The organic solvent layer is washed to neutrality with water, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a solid residue of the requisite intermediate, 6-chloro-7-iodo-9B, -1 lfi-epoxy-1701,21-dihydroxy-4-pregnene 21-acetate.

Without further purification, the 6-chloro-7-iodo-4- pregnene is dissolved in 200 ml. of 2,4-lutidine and refluxed 30 minutes, then evaporated in vacuo to a solid residue which is crystallized from aqueous acetone to yield 6 chloro 95,115 epoxy 17,21 dihydroxy- 4,6-pregnadiene-3,ZO-dione 21-acetate; 7r max.=297 mu (CH OH). C. G-CHLOR-O-Qa-BROMO-G-DEHYDROHYDROCORTISON ill-ACETATE One gram of 6-chloro-9fi,11p-epoxy-17a,2l-dihydroxy- 4,6-pregnadiene 21-acetate (prepared as in Example 11B) is dissolved in 20 ml. carbon tetrachloride and 20 ml. of glacial acetic acid, and 0.63 ml. of 4-Normal hydrobromic acid in acetic acid is added while maintaining a reaction mixture temperature of approximately 15 C. Twenty minutes after the addition is complete, the solution is diluted with 50 ml. of methylene chloride and washed to neutrality with water. The organic solvent layer is dried over magnesium sulfate, filtered, and evaporated in vacuo to a residue which is crystallized and recrystallized from aoetonehexane to give 6-Chl'OIO-90cbr-omo-6dehydrohydrocortisone 21-acetate, A max.=297 a (CH OH).

D. -6-CHLOR0-9aBROMO'6-DEHYDROHYDROCORTISONE The 21-acetate of Example 11C is hydrolyzed in the manner of Example 301 to give 6-chloro-9a-bromo-6- dehydrohydrocortisone.

10 EXAMPLE 12 6-br0m0-9a-chl0ro-6-dehydrohydrocortisone The requisite intermediate, 6,7-dibromo-96,1I/B-epoxy- 170:,21 dihydroxy 4 pregnene 3,20 dione 21 acetate, is prepared in the manner of Example 1 from 9 3, 115 epoxy 17,21 dihydroxy 4,6 pregnadiene- 3,20-dione 21-acetate (prepared as in Example 11A) and bromine.

The crude 6,7-dibromide thus prepared is dissolved in 100 ml. of acetone and 4 grams of potassium acetate added. The reaction mixture is refluxed 20 hours, then evaporated to dryness. The resultant residue is triturated with water, filtered, washed further with Water, dried, then crystallized from acetone to give 6-bromo-9{3,l1flepoxy 170:,21 dihydroxy 4,6 pregnadiene 3,20- dione 21-acetate, max.=299 ,u. (CH OH).

B. G-BROMO-Qa-CHLORO-G-DEHYDROHYDROCORTI-SONE 21-ACETATE A solution of one gram of 6-bromo-9p-llp-epoxy- 17u,21 dihydroxy-4,6 pregn-adiene 3,20-dione. 21-acetate (prepared in Example 12A) in 20 ml. of freshly distilled chloroform is cooled to 25 C. To this is added 6.3 ml. of a 0.4 normal solution of hydrogen chloride in chloroform also cooled to -25 C. The reaction mixture is allowed to stand at 0 C. for two hours, and is then extracted with water to neutrality. The organic solvent layer is concentrated to dryness and the residue crystallized and recrystallized from acetone to give 6- bromo 9oz chloro 6 dehydrohydrocortisone 21 acetate, A max. =298 ,u. (CH OH).

C. 6-BROMO-9a.CHLORO-DEHYDROHYDROCORTISONE The 2l-acetate of Example 12B is hydrolyzed in the manner of Example 301 to give 6-bromo-9a-chloro-6- dehydrohydrocortisone.

EXAMPLE 13 6-br0m0-9a-chl0r0-6-dehydr0cortisone EXAMPLE 14 6-br0m0-6-dehydrohydrocortisone 11,21-diacetate 1 7-pr0pi0nate A. HYDROCORTISONE 11,21-DIACETATE 17-PROPIONATE Tto 9.0 g. of hydrocortisone 11,21-diacetate is added 450 ml. of propionic acid. The reaction mixture is saturated with argon, and the solution warmed to approximately 90 C. Trifluoroacetic anhydride ml.) is added and the temperature maintained at 85-90 C. for 45 minutes. The reaction solution is cooled, poured into 10 liters of cold Water, and allowed to stand for 1 hour. The precipitated organic material is then separated by filtration, washed three times with 50 ml. of water, dried at 60 C., and crystallized from acetone-hexane to give hydrocortisone 11,21-diacetate 17-propion-ate. B. G-DEHYDROHYDROCORTISONE '11,21-DIACETATE 17-PROPIONATE The requisite intermediate, 6-bromohydrocortisone 11., 21-diacetate 17-propionate, is prepared from 5 g. of the tri-ester of Example 14A and 1.9 g. of n-bromosuccinimide in the manner described in Example 8A. The resultant 6-bromohydrocortisone tri-ester is dehydrobrominated with 2,4-lutidine in.the manner of Example 8A= and a product. isolated which, when crystallized from acetone-hexane, gives 6-dehydrohydrocortisone 11,21- diacetate l7-propionate.

C. 6-BROMO-6-DEHYDROHYDROCORTISONE 11,21-

' DIACETATE'17-PROPIONATE In the manner of Example 1, 2.5 g. of the 6-hydrohydrocortisone of Example 14B is reacted 'with 0.85' g. of bromine to yield a residue of.6,7-dibromol1ydrocortisone 11,21-diacetate 17-propionate.

.. This isolated dibromide'gis dissolved in 2,4-lutidine (60 ml.) and refluxed 45 minutes. The reaction solution EXAMPLE .15

6-br0mo-6-dehydroprednis0ne 21-acetate The requisite intermediate, 6,7-dibromoprednisone 21'- 'acetate, is prepared from 6-dehydroprednisone 21-acetate:

in the following manner. To a vigorously stirred solution' of 1g. of 6-dehydroprednisone 21-acetate in 350.

ml. of methylene.- chloride, there is added 3 drops of a solution of hydrobromic. acid in acetic acid followed-by the dropwise addition, over a 35 minute period, of 0.41 g. of bromine in 40 ml.'of methylene chloride. organic solution is then Washed with water (()ml.) sodium carbonate (50 ml.) and again with water. The .organic solution is dried over magnesium sulfate, filtered and evaporated to a residue comprising 6,7-dibromoprednisone ZI-acetate. This residue is used without.

further purification in the following procedure.

To the dibromide prepared above, there is added under argon gas 20 ml. of 2,4-lutidine and the mixture isheated The reaction mixture is then 1 at 90-95 C. for 3 /2 hours.

The

cooled and poured into a slight excess of dilute ice-chilled aqueous sulfuric acid and the acidified mixture is ex tracted twice with methylene chloride. The organioextracts are combined, washed with water, dried :over

magnesium sulfate and filtered. The filtrate is evaporated 1 to a small volume (3 ml.) and poured onto a magnesium silicate column (40 g.) saturated with'hexane. The fractions eluted with 40-50% of ether in hexane are combined and evaporated to a residue which is crystallized from acetone-hexane to give 6-bromo-6-dehydroprednisone.- 2l-acetate, M.P. 241-242 C., A max. 226 and 309 mu (CH OH).

Alternatively the compound of this example is prepared acetate (the compound of Example 1) in 160 ml. of

t-butanol and 1.7 ml. of acetic acid. Selenium dioxide (1.7 g.) is added and the solution is refluxed under nitrogen for 8 hours. An additional 1.7 g. of selenium dioxide is then added and refluxing is maintained for an additional 11 hours The solution is then cooled, filtered and-evaporated to a residue which is dissolved in 20.0 ml. of methylene chloride. The organic solution is washed twice with '50 ml. portions of 1 N-sodium hydroxide, twice with SOmL-portions of water and is then dried over magnesium sulfate, filtered and evaporated to a residuewhich is chromatographed using magnesium silicate as described. in the above alternative procedure to give 6-bromo-6-dehydroprednisone 21-acetate.

by dissolving 3 g. of 6-bromo-6-dehydrocortisone 21- 1'2 (3) A second alternative method for preparing the compound of this example. from 6-bromo-6-dehydrocortisone ZI-acetate. (the. compound of Example 1). is by the,

microbiological oxidation with Corynebacterium simplex (A.T.C.C. 6946 as described in U.S. Patent No.

2,837,464; From a solution of 30 g. of yeast extract .(Difco) in 3.01. of tap water containing 13.2 g. of potassium dihydrogen phosphate and 26.4 g. of disodium hydrogen phosphate (pHof the solution 6.9) 27iportions ofml. each are withdrawn, "placed. l111i300 ml. Erlenmeyer flasks and sterilized by autoclaving for 15 minutes at 15 lb. steam pressure 0.). After .autoclaving'and cooling'of the broth one ml. of a suspension of Corynebacterium sim plex (A.T.C.C. 6946) is placed in each flask. The flasks:

are then. shaken on a shaketable at-220 r.p.m. and 36 C. for 24 hours.

Into each of 27. Erlenmeyer flasks are placed mg. of 6-bromo-6-dehydrocortisone ZI-acetate. The flasks and contents are then sterilized for 15 minutes at 15 lb. steam pressure (120 C-.).

transferred asceptically andthe resulting suspensions are shaken on a shake'table at 220 r.p.m. and 36 C. for 48 hours.v The final pH is}7.2.

The contents of all the flasks are combined andextracted withpa totaltof 9 l. of chloroform in three equal The. combined extracts. are then concentrated.

portions. to a residue which is crystallizedfrom acetone-hexane to give 6-bromo-6-dehydroprednisonev 21-acetate, 241- 242 C.

EXAMPLE? 16 I 6-bromor6-dehydroprednisone 6-bromo-6-dehydroprednisone ZI-acetate, prepared as in Example 15,=ishydrolyzed to the corresponding 21-alcohol with dilute aqueous sodium hydroxide .under argon gas in the manner described in Example 2 to give 6-bromo- 6-dehydroprednisone..

EXAMPLE 17 6-bromo-6 dehydroprednisolone.

The requisite intermediate, 6,-7-dibromoprednisolone 21-acetate, is prepared from .6-dehydroprednisolone .21- aceta'te. and-bromine; in methylene chloridein the manner described in Example .15.

6,7-dibromoprednisolone 21-acetate, prepared as de scribed above, is reactedwith ZA-lutidine in the manner described in Example 15 and the resultant product. isolated and 'purified'in the. described :manner. to give 6-bromo-6-dehydroprednisolone' ZI-acetate.

Alternatively, 6-bromo-6-dehydroprednisolone f2l-acetate is' prepared. by reacting 6-ibromo-6-dehydrohydrocortisone ZI-acetate .(the compound of Example 4) with selenium dioxide under nitrogenandthe resultant prod-.

not: isolated and 'purifiedas described in the. alternative. procedure of Example 15.

A second. alternative methodfor preparing .6-bromo- I 6-dehydroprednisolone ZIi-acetateis by the microbiological. oxidation of. 6-bromo-6-dehydrohydrocortisone 21- acetate. (the compound of Example .4) with Corynebacterium simplex as described in US. Patent No. 2,837,464.

6-bromo-6-dehydroprednisolone ZI-acetate is hydrolyzed to the. corresponding 21'-alcohol with aqueous sodium hydroxide solution -in chloroform-methanol as described in Example 2 'to give ,6-bromo-6-dehydroprednisolone.

EXAMPLE; 18 I The requisite intermediate, 6,7-dibromo-9a-fluorocortisone ZI-acetate, is prepared by reacting 9m-fluoro-6-dehydrocortisone ZI-acetate. with hydrogen. bromide. and bromine in :the .manner of Example 8B? The dibromide I thus prepared isfurther reacted with 2,4-lutidinein the To each flask arethen added 5.0 ml. of ethanol. The 24-hour bacterial culture is then.

manner of Example 1 to give 6-bromo-9a-fluoro-6-dehydrocortisone 21-acetate.

6'-bromo-9a-fluoro-6-dehydrocortisone 21-acetate is hydrolyzed to the Corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in chloroform-methanol in the manner of Example 2 to give 6-bI0II10-9oc-fll10l'0- G-dehydrocortisone. Alternatively, 6-bromo 9oz fluoro-G-dehydrocortisone 2l-acetate is prepared as follows:

To a solution of 0.3 g. of 6-bromo-9a-fluoro-6-dehydrohydrocortisone 2l-acetate (a compound of Example 9) in 15 ml. of acetic acid there is added dropwise a solution of 60 mg. of chromium trioxide in 1 ml. of waterand 3 ml.

of acetic acid. The resultant mixture is allowed to stand for 5 hours and then is diluted with water and extracted with methylene chloride. The organic extracts are Washed with water, dried over magnesium sulfate, filtered and evaporated to a residue which is crystallized from acetonehexane to yield 6-bromo-9a-fluoro-6-dehydrocortisone 21-acetate.

.EXAMPLE 19 The requisite intermediate, 6,7-dibromo-9a-fluoroprednisone Ill-acetate, is prepared in rthe manner of Example from 9a-fluoro-6-dehydroprednisone 21-acetate and bromine in methylene chloride.

The 6,7-dibromo-9a-fluoroprednisone 21-acetate prepared as described above is reacted with 2,4-lutidine under argon gas in the manner described in Example 15 to give 6-bromo-9a-fluoro-G-dehydroprednisone 21-acetate. I

Alternatively, the 2l-acetate of the compound of this example is prepared from 6-bromo-9u-fluoro-6-dehydrocortisone 21-acetate (prepared as in Example 18) by oxidizing with selenium dioxide under nitrogen or by the action of a culture of Corynebacterium simplex as described in the alternative methods of Example 15 6-bromo-9a-fluoro-6-dehydroprednisone 2l-acetate, prepared as described above,'is hydrolyzed to the corresponding 2l-alcohol with dilute aqueous sodium hydroxide in chloroform-methanol in the manner of Example 2 to give 6-bromo-9a-fluoro-6-dehydroprednis=one.

EXAMPLE 20 6-brom0-9a-fliz0ro-6-aehydroprednisolone The requisite intermediate, 6,7-dibromo-9a-fluoroprednisolone 21-acetate, is prepared by brominating 9a-fluoro G-dehydroprednisolone 2l-acetate in the manner described in Example 15. I

6,7-dibromo-9a-fluoroprednisolone 2l-acetate is dehydrobrominated with 2,4-lutidine in the manner described in Example 15 to give 6-bromo-9u-fluoro-6-dehydroprednisolone ZI-acetate.

Alternatively, the 2l-acetate of the compound of this example is prepared by oxidizing 6-brorno-9a-fluomo-6-dehydrohydrocortisone ZI-acetate (a compound of Example 9) with selenium dioxide or by the action of a cultureof Corynebacterium simplex according to the alternate procedures of Example 15 to give 6-bromo-9a-fluoro-6-dehydroprednisolone 21-acetate.

The ZI-acetate of the compound of this example is hydrolyzed to the corresponding 21-alcohol with dilute aqueous sodium hydroxide in chloroform-methanol in the manner of Example 2 to give 6-bromo-9a-fluoro-6-dehydroprednisolone.

- EXAMPLE 21 6,9m-dibr0m0-6-dehydroprednisolone A. 9 5,115-EP0XY-17 a,21-DIHYROXY-1,4,G-PREGNA- TRIENE-3,20-DIONE 21-ACETATE The requisite intermediate, 6-b-romo-9 3,llfl-epoxy- 17a,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acetate, is prepared in the manner of Example 8A from 95,115- epoxy-l7u,21-dihydroxy-1,4-pregnadiene-3,20-dione 21- acetate and N-bromosuccinimide.

The 6-bromo-9/3,11B-epoxy intermediate thus prepared is dissolved in 200 ml. of 2,4-lutidine and reacted in the manner of Example 8A to give 9B,11 8-epoxy-17u,21-dihydroxy-l,4,6-pregnatriene-3,204li'one 21-acetate.

B. G-BROMO-QB,1IB-EPOXYJFM,21-DIHYDROXY-1,4,6-

PREGNATRIENE-3,20-DIONE 21-ACETATE The requisite intermediate, 6,7-dibromo-9fi,1lfl-epoxy- 17u,2l-dihydroxy-l,4-pregnadiene-3,ZO-dione 2l-acetate, is prepared in the manner of Example 1 by brominating 95,1113 epoxy-l7a,2 l-dihydroxy-l,4,6 pregnatriene-3,20- dione 21-acetate (the compound of Example 21A).

The 6,7-dibromo-9fi,l1,B-epoxy thus prepared is dissolved in ml. of acetone and 4 g. of potassium acetate added. The reaction mixture is refluxed 20 hours, then evaporated to dryness. The resultant residue is triturated with water, filtered, washed further with water, dried, then crystallized from acetone to give 6-bromo-9/3,11B-epoxy- 17a,2l-dihydroxy-l,4,6-pregnatriene-3,20-dione 21-acetate.

- Alternatively, the compound of this example is prepared from 6-bromo-9{3,11,8-epoxy-17u,21-dihydroxy-4,6-pregnadiene-3,20-dione 2l-acetate by the oxidizing action of a culture of Corynebacterium simplex according to procedures analogous to those described in US. Patent No. 2,837,464.

C. 6,Qa-DIBROMO-6-DEHYDROlE'REDNI-SOLONE 21-ACETATE One gram of 6-bromo-9fl,1lfi-epoxypregnatriene, prepared as in Example 21B is dissolved in 20 ml. of carbon tetrachloride and reacted with hydrobromic acid in acetic acid in the manner of Example 11C. The resultant prodnet is isolated and purified in the described manner to give 6,9oc-dibromo-6-dehydroprednisolone 2l-acetate.

D. 6,9a-DIBROMO-'6 DEHYDROPREDNISOLONE A solution of 2 g. of 6u-fluoroprednisone in 10 ml. of pyridine and 10 ml. of acetic anhydride is left at room temperature for fifteen hours. The mixture is then poured into ice and water. A solid separates which is washed with water, filtered, air dried and crystallized from acetonehexane to give 6a-fluoroprednisone 21-acetate.

B. -6BROMO-6FLUOROPREDNI SONE 21-ACETATE To a solution of 2.0 g. of 6a-fluoroprednisone 21-acetate in 250 ml. of carbon tetrachloride and 250 ml. of chlorobenzene under an atmospher of nitrogen there is added 0.92 g. of freshly crystallized N-bromosuccinimide. The refluxing solution is illuminated with an incandescent lamp (RFL No. 2) until the reaction solution is negative to starch iodide paper. The solution is chilled, washed with .water, dried over magnesium sulfate, filtered, and concentrated in vacuo to a residue which is crystallized from acetone-hexane to give 6-bromo-6-fluoroprednisone 21- acetate.

C. (S-FLUORO G-DEHYDROPREDNISONE 21-ACETATE To 15 ml. of 2,4-lutidine under nitrogen there is added 0.5 g. of 6-bromo-6-fluoroprednisone 21-acetate (the compound of Example 22B). The solution is refluxed for 2 hours, then cooled and poured into an ice-cold water solution containing 10 ml. of sulfuric acid. The reaction mixture is extracted with methylene chloride, the organic extracts are combined, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to a residue which is chromatographed over magnesium silicate. The fractions containing 40%80% ether-in-hexane are combined and concentrated in vacuo to give 6-fluoro-. 6-dehydroprednisone 21-acetate.

D. '6-FLUOR O-G-DEHYDROPREDNISONE The 21-acetate of Example 220 is hydrolyzed to. the corresponding 2l-alcohol by means of dilute aqueous sodium hydroxide in the manner described in Example 2 to give 6-fluoro-6-dehydroprednisone.

Alternatively, the compound of this example is prepared as follows. 6-fiuoro-6-dehydrocorti-sone 21-acetate' (the compound of Example 7) is subjected to the action of a culture of Corynebacterium simplex and the resultant product isolated and purified in a manner similar to-that' described in Method 3 of Example 15 to give 6-fluoro-6- dehydr'oprednisone 2l-acetate. Hydrolysis of this 2l-acetate to the corresponding 2l-alcohol in the manner of EXAMPLE 23 6-chloro-6-dehydroprednisone 21 acetate A. 541,641-OXIDO-l-PREGNENE-l7:1,21-DIOL-3,11,20- TRIONE 21-ACETATE The requisite intermediate, 1,S-pregnadiene-17,21-di01 3,11,20-trione 2-l-acetate, is prepared as described incopending application Serial No. 725,521 of Nussbaurn et al., filed April 1, 1958, now abandoned.

A solution of 4 g. of 1,5-pregnadiene- 17e,211-dio1- 3,11,20-trione 2l-acetate in 600 ml. of benzene is cooled to 6-8 C., and then there is added a solution of,35 ml.

of 40% peracetic acid and 3.5 g. of sodium acetate. The

mixture is allowed-to stand overnight at room temperature. The benzene layeris then separated, washed with dilute sodium hydroxide and water, dried over magnesium sulfate, and evaporated to a residue Which is crystallized from acetone-hexane to give a,6u-o-xido-1-pregnene- 17a,Z1-di0l-3,1 1,20-trione 2l-acetate.

B. 'Ga-CHLOROPREDNISONE 21-ACETATE 5a,6a-oxido-1-pr egnene-17a,21-diol-3,11,20 trione 21- acetate (1.0 g.), the product of Example 23A, is dissolved in 20 ml. of freshly distilled chloroform and chilled to -20 C. and there is added 6.2 ml. of a 0.4 N solution: of anhydrous hydrogen chloride in chloroform, also chilled to 20 C. The reaction solution is allowedtostand at 0 C. for 2 hours, then the excess acid iswashed free with water. The chloroformlayer is dried over magnesium sulfate, filtered, then chilled in an ice-salt bath. The organic solution is saturated with hydrogen chloride for 45 minutes, then is washed neutral with water,

dried and evaporated to a residue which is crystallized from methanol-water to give 6OLCh;lQI'OPl'6dI1lSOI1 21- acetate.

C. B-CHLOROJi-BROMOPREDNISONE 21-ACETATE A solution of 2.0 g. of 6u-chloroprednisone 21-acetate is. treated with Nsbromosuccinimide and the resultant producti-solated and purified in the manner described in Example 22B to give 6-chloro-6abromoprednisone 21- acetate.

D. 'G CHLORO-6-DEHYDROPREDNISONE 21-ACETATE In a manner. similar to thatdescribed in Example 22C, 0.5 g. of the6-bromo-6-chloroprednisone21-acetate of Example 23C, is reacted with 15 ml. of 2,4-lutidine at reflux for two hours. The tresultant product isisolated and purified inthe described manner to give 6-chloro-6-dehy-- droprednisone 21-acetate.

Alternatively, 6a-cl1loroprednisone :21-acetate, the compound of Example 233 is prepared asdescribed in the followingprocedures E, F, G, H, and I.

E. .CORTI-SONE 2l-ACETATE 3-ETHYLENE KETAL A solution; of- 2 g. of gcortisone 'ZI-acetatein 25 ml. of chloroform containing 50 m1.- of ethylene glycol and '100 mlhof p-toluenesulfonic acid is concentrated with stirring at atmospheric pressureuntil the temperature reaches 75 C. The last traces of=chloroform.are then removed in vacuo. The mixture is cooled, and tone ml.

of pyridine .is-added, followed by=150 ml. of. 2% aqueous; sodiumbicarbonatesolution; The mixture is extracted with methylene; chloride. Theor-ganic' layer is washed several times with water, dried over magnesium sulfate and evaporated to a residue which is crystallized from acetoneehexane to give ,cortisoneZL-aoetate 3-ethylene ketal.

F. 5a,6a-OXIDOPREGNANE-17a,21-DIOL-3,11,20-TRIONE 21-ACETATE. 3-ETH'ZLENE KETAL 850mg. of the 3-ethylene ketal of Example 23B is dissolvedinsl5 'ml. ofJchloroform,.and there is added a mg. of sodium acetate'and 1 ml. of 40% peracetic acid. After standing for two hours, the solution is washed 1 with cold dilute sodium hydroxide and water, then dried over magnesium sulfate and evaporated to a residue.

which is'crystallized from acetone-hexane to yield 50,6a-

oxido'pregnane-l70;,211-di0l-3,1,l,20rtrione 21 acetate 3- ethylene ketal.

G. GB-CHLOROCORTISONE 21 -A'CETATE A solu-tion'of 1 g. of the oxido-pregnane prepared in Example 23'Frin 20 ml'.'of chloroform is chilled to 20 C. and .there is added 6.2 'ml.'of*a 0.4 N solu- I tion of anhydrous hydrogen chloride in chloroform also chilled to -20-' C. .The reaction solution is allowed to stand at 0 C. for two hours, then the excess acid is washed free with water. 1' The chloroform layer is dried over magnesiumsulfate and evaporated to. a residue. To'

this residue there. is added 50 ml. of acetic; acid and 1 ml. of Water. The solution is refluxed for two hours, cooled and diluted with water, then extracted with methylene chloride. The organic extracts are combined,- Washed 3 to neutrality with water, dried overs magnesium sulfate, then evaporated to a residue whichjs crystallized from acetone to give 6-fl-chlorocortisone ZI-acetate;

H. Sa-CHLOROCORTISONE -21-ACETATE A solution of, lOO-mg. of the 6fl-chlorocortisone 21-. acetate of Example 236 in 10 ml. of chloroform is cooled to -10? C., and a stream of anhydrous hydrogenchloride is-introduced during a period of 2 hours while main- I tainiug the temperature at -10= C. The chloroform solution is then washed-with sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated to a residue which is crystallized from acetone-hexane to give Ga-chlorocortisone 21-acetate.

I. BwCHLOROPREDNISONE .21-ACET-ATE 6ot-chlorocortisone .ZLacet-ate, .the compound of Example 23H, is subjected to the action ofCorynebacterium simplex in {the manner described .i-n procedure -310f Example 15, and the product is isolated i'ntheidescribed manner to give 6a-chloroprednisone 21-acetate,

A third method for the preparation of the compound ofthis exampleis by subjecting ;6-chloro-6-dehydrocortisone Zl-acetate, the ,compound of Example 5, to the action of Corynebacterium simplex in a manner similar 17 to that of procedure 3 of Example 15. The resultant product is isolated and purified in the described manner to give Got-ch10ro-6-dehydroprednisone 2-1-acetate.

EXAMPLE 24 6-chlo ro-6-dehydr0prednisone 6-chl-o-ro-6-dehydroprednisone 21-acetate, the compound of Example 23, is hydrolyzed to the cor-responding 21-alcohol in 1:2 chloroform-methanol by means of dilute aqueous sodium hydroxide in the manner in Example 2 to give 6-chloro-6-dehydroprednisone.

EXAMPLE 25 6-flu0r0-6-dehydropirednisolo ne A. Ga-FLUOROPREDNISOLONE 21-ACETATE 6a-fluoroprednisolone is reacted with acetic anhydride in pyridine and the resultant product isolated and purified in the manner described in Example 22A to give 600- fiuoroprednisolone 21-acetate.

B. G-BR OMO-GJELUOR OPREDNISOLONE 21'ACE'IATE C. G-FLU ORO-G-DEHYDROPREDNISOLONE ill-ACETATE 6-bromo-Gdiuoroprednisolone 21-acetate, the compound of Example 25B, is reacted with 2,4-lutidine under nitrogen and the resutant product isolated and purified in the manner described in Example 22C to give 6-tflu0ro- 6-dehydroprednisolone ZI-acetate.

D. 6-FLUORO-6-DEHYDROPREDNISOLONE The ZI-acetate of Example 25C is hydrolyzed to the corresponding 21-.alcohol in 1:2 chlorofornvmethanol with dilute aqueous sodium hydroxide in the manner described in Example 2 to give 6 fluoro-6-dehydropredn-isolone.

EXAMPLE 26 6,9a-diflur0-6-dehydroprednisolone A. G-BROMO6,9a-DIFLUOROPREDNISOLONE ZLACETATE 6,9a-difluoroprednisolone 21-acetate is dissolved in dioxane and reacted with bromine in dioxane and the resultant product isolated and purified in the manner described in Example 258 to give 6-bromo-6,9u-difluoroprednisolone 21-acetate.

B. 6,9a-DIFLUORO-G-DEHYDROPREDNI SOLONE 21 ACETATE The 6 bromo-6,9a-difluoroprednisolone 21-aceta-te of Example 26A is reacted with 2,4-lutidi-ne under an atmosphere of nitrogen and the resultant product isolated and purified in the manner described in Example 22C to give 6,9u-difiuoro-fi-dehydroprednisolone 21-acetate.

C. 6,9a-DIFLUORO-ti-DEHYDROPREDNISOLONE The 21-acetate of Example 26B is hydrolyzed to the corresponding ll-alcohol in 1:2 chloroform methanol with dilute aqueous sodium hydroxide in the manner of Example 2 to give 6,90:-diiiuoro-6-dehydroprednisolone.

EXAMPLE 27 6,9a-diflu0r0-6-dehydropreanisone A. 6-BROMO-6,9a-DIFLUOROPREDNISONE 21-ACETATE 6,9a-difluoroprednisone 2l-acetate dissolved in carbon tetrachloride and chlorobenzene is reacted with N-bromosuccinimide under nitrogen in the manner described 18 in Example 22B, and the resultant product isolated and purified in the described manner to give 6-bromo-6,9adifluoroprednisone 21-acetate.

B. 6,9a-DIFLUORO-6-DEHYDROPREDNISONE 21-ACETATE The 6-bromo-6,9a-difiuoroprednisone 21-acetate of Example 27A is reacted with 2,4-lutidine under nitrogen and the resultant product isolated and purified in the manner described in Example 22C to give 6,9OL-dlfl1101'0' 6-dehydroprednisone 2l-acetate.

C. 6,9a-DIFLUORO-G-DEHYDROPREDNISONE The 21 acetate of Example 27B is hydrolyzed to the corresponding 21-alcohol in 1:2 chloroform-methanol with dilute aqueous sodium hydroxide in the manner of Example 2 to give 6,9a-diiiuo-ro-6-dehydroprednisone.

Alternatively, the compound of this example is prepatried'lgy meaoting 6,9oc difluopo-6-dehydroprednisolone 121-acet'afte, the compound of Example 26B, with chromic 'facid i acetic acid in the manner described in Exam- A. 6-FLUORO-1,4,6,9 (11)-PREGNATETRAENE-l7a,21- DIOL-3,20DIONE 2l-ACETATE Five grams of 6-fluoro-6-dehydroprednisolone 21- acetate, the compound of Example 25C, is dissolved in 20 ml. of dry dimethylformamide and 4 ml. of dry pyridine. The solution is chilled in an ice-bath and to it is added dropWise 2.8 g. of methanesulfonyl chloride which has been diluted to 30 ml. with dimethylformamide. After the addition has been completed, stirring is continued at room temperature for 48 hours. The reaction mixture is then poured into cold dilute sulfuric acid and the precipitate which forms is filtered, air dried and crystallized from methanol to yield 6-fiuoro- 1,4,6,9(11)-pregnatetraene-17a,21 diol-3,20-dione 21- acetate.

B. 6-FLUORO9a-BROMO-6-DEHYDROPREDNISOLONE 21-A'CETA'TE 1.25 g. of the 6afiuoropregnatetraene of Example 28A is dissolved in 19%. ml. of methylene chloride and there is added 38 ml. of t-butyl alcohol as well as a solution of 3 ml. of 72% perchloric acid in 22 /2 ml. of water and a solution of 0.55 g. of N-bromoacetamide in 9 /2 ml. of tbutyl alcohol. The solution is stirred /2 hour and a solution of 0.55 g. of sodium sulfite in 30 ml. of Water is added, and the mixture concentrated in vacuo -to a residue. The residue is dissolved in methylene chloride and chromatographed on a magnesium silicate column, then eluted with ether in hexane. The eluates containing 30-60% ether in hexane are combined and concentrated to a residue which is crystallized from acetone-hexane to give 6 fluoro-9a-bromo-o-dehydropred- V nisolone 21-acetate.

o. G-FLUOR0-9a-BROMO-G-DEHYDROPREDNISOLONE The 21-acetate of Example 28B is hydrolyzed to the corresponding 21-alcohol by means of methanolic perchloric acid in the manner of Example 21D to give 6- fluoro-9a-bromo-6-dehydroprednisolone.

EXAMPLE 29 6-chl0r0-6-dehydr0prednisolone A. 5:1,6a-OXIDO-l-PREGNENE-11fi,17a,2l-TRIOL- 3,20-DIONE ZI-ACETATE with 35 m1. of 40% peracetic acid and 3 /2 g. of sodium ace'tatte and the resultant product is isolated and purified. in the manner described in Example 23A to give 50:,6a-

oxido-l-pregnene-l 1/3, l.7a,2l-triol-3,20-dione ZI-acetate. B. GwCHLOROPREDNISOLONE ZI-ACETATE The 5a,6a-oxido-'1a regnene of Example 29A is dissolved -in chloroform and reacted with anhydroushydrogen chloride in the manner of Example 23B to give 60cchloroprednisolone 21 acetate.

C. 6-'CHLORO6-BROMOPREDNISOLONE 21-ACETATE A solution of 2 g. of 6a-chloroprednisolone 21-acetate,

the compound of Example 29B, is reacted with bromine in dioxane and the resultant product isolated and purified in the manner described in Example 25B to give 6-chloro-,

6-bromoprednisolone ill-acetate.

' D. G-CHLORO-G-DEHYDROPREDNISOLONE ZLACETATE 6-bromo 6 chloroprednisolone 21 acetate, the compound of Example 29C, is reacted with 2,4-lutidine in the manner of Example 22C and the resultant product isolated and purified in the described manner to give 6- chloro-6-dehydroprednisolone Zl-acetate.

E. G-CHLORQ-G-DEHYDROPREDNISOLONE The ZI-acetate of Example 29D is hydrolyzed to the corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6-chloro-6-dehydroprednisolone.

A; 6-BROMO-6-FLUORO-1GQ-METHYLHYDROCORTISONEl 2l-ACETATE The requisite intermediate, .6a-fiuoro-l6a=methylhydrocortisone ZI-acetate is prepared in the manner described in co-pending application Serial No. 770,288 of Nussbaum et al., filed October 29, 1958.

6a-fluoro-l6cc-methylprednisolone 21-acetate is reacted with bromine in dioxane under nitrogen and the resultant product isolated and purified as described in Example 2513 to give 6-bromo-6-fluoro-l6nmethylhydrocortisone 21-acetate.

B. 6-FLUORO 16a-METHYL-G-DEHYDROHYDROCORTI- SONE 21-ACETATE 6-bromo-6-fluoro-16ix-methylhydrocortisone ZI-acetate, the compound'of Example 30A, is reacted with 2,4-lutidine under an atmosphere of nitrogen and the resultant .1 product isolated and purified in the manner described.

in Example 22C to give 6-fiu0r0-16a-methyl-6-dehydrohydrocortisone 2l-acetate.

C. 6-FLU OR O-l6a-\IETHYL-ii-DEHYDROHYDRO- CORTISONE The ZI-acetate of Example 30B is hydrolyzed to the.

corresponding 2l-alcoh0l by means of dilute aqueous sodium hydroxide in the manner describedin Example 2 to give 6-fiu0ro-l6a-methyl-6-dehydrohydrocortisone.

Alternatively, the compound of this example may be prepared as described in the folowing procedures D, E,

F. G. H, and I.

D. 16a-METHYLHYDROCORTISONE TRIACETATE.

The requisite intermediate, l6a-methylhydrocortisone 2l-acetate, is prepared from 16-pregnene-3ot-ol-11,20- dione in the manner described in co-pending application Serial No. 733,843 of Rausser et al., filed May 8, 1958,

now US. Patent No. 3,164,618.

To 9 g. of l6a-methylhydrocortisone 2l-acetate there is added 450 ml. of acetic acid.- The reaction mixture is saturated with argon gas and the solution war-med to-approximately. 90 C. Trifluoroacetic anhydride m1.) is added and the temperature maintained at 8590 longer, if desired),

, C. for 45 minutes. The reaction solution is cooled, poured The triacetatehof Example 30D is reacted with N- bromosuccinimide in carbon: tetrachloridemnder an atmosphere of nitrogen and .the resultant product isolated and purified in the manner described in Example 8A to give 6-bromo-16u-methylhydrocortisone, triacetate.

I l6a-\IETHYL-6-DEHYDR OHYDRQCORTISONE TRIACETATE 6-brorno-16a-methy1hydrocortisone triacetate,.the com. pound of Example 30E; is. reacted with 2,4-lutidine and the resultant productisolated and purified in the manner give .l6u-methyl-6-dehydroa described in Example 8A to hydrocortisone .triacetate:

G. 6-FLUOR-O-7-BROMO-1Gil-METHYLHYDROCORTISONE TRIACETATE.

16a methyl 6 dehydrohydrocortisone triacetate, the compound of Example 30F, is reacted with hydrogen fluoride .and iN-bromoacetamidc in'frmethylene chloride,

and the resultant product isolated and purifiedin the manner described in Example -7 to give 6-fluoro-7-bromo-l6mmethylhydrocortisone' triacetate.

H. ,G-FLUORO-lGIZ-RIETHYL G-DEHYDROHYDROCORTI- SONE TRIACETATEi In the manner of Example? 7," 6-fluoro-7-bromo-16amethylhydrocortisone triacetate is reacted with 2,4-1uti-1 dine under argon gas and the .resultant' product isolated and purified to give 6-fluoro-16ot-methyl-6-dehydrohydro cortisone triacetate,

I. G-FLUORO l6aMETHYL-6-DEHYDROHYDRO- CORTISONE Thetria'cetate of Example 30H is hydrolyzed to the corresponding trihydroxy-compound with the;aicl of a culture of Flavobacterium dehydrogenans (RutgersiUniversity'Collection No. 130). V V

The culture of the; organism is prepared by propagating it in a nutrientragar medium at 30 .C. for 24 to 72 hours. During incubation, thevinoculated tube is eX- posed to light with the resultantdevelopment of a yellow pigment characteristic of the species. The developed cultureis rinsed froman agar. slant under sterile conditions into a sterile mediumof pH 6.8 and having the following composition:

Gm. Yeast extract (Difco) 10 Potassium phosphate .monobasic 4.48 Sodium phosphate dibasic 4.68

Tap water to 1 liter.

This culture medium has. previously beeniautoclaved,'

as at 15 lb. pressure, for twenty minutes to obtain aseptic condtions, and. cooled The variant is grown in the medium under' constant illumination, using the visible rangexof the spectrum. The incubation temperature is maintained atabout 33C. and is;conducted under aerobic conditions. Aeration is-accomplished zby agitation and/or blowing air, through the culture medium.

Afterthe organism has grown ;for 12 to 24 hours. (or

introduced into each of ten flasks, andto teach flask are added 200 mgpof 6-fluoro-16m-methyl-6dehydrohydrocortisone triacetate dissolved in a minimum volume of ethanol. The reaction .mixtures are then shaken at 30 C. for 12 to 48 hours. The reaction is stopped when paper chromatography indicates-that the starting material has been transformed.

ml.. of the growing culture are 21 The contents of the flasks are combined and extracted with methylene chloride. The extracts are concentrated to a residue which is crystallized from acetone-hexane to give 6-fiuoro 16a methyl-6-dehydrohydrocortisone 21- acetate.

EXAMPLE 31 6-flu0r0-16a-methyl-6-dehydrocortisone A. G BROMO-G-FLUORO-lGa-METHYDCORTISONE 2l-ACETATE The requisite intermediate, Got-fluoro-16m-methylcortisone 21-acetate, is prepared as described in co-pending application Serial No. 770,288 of Nussbaum et al., filed October 29, 1958.

6a-fluoro-16a-methylcortisone 21-acetate and N-bromosuccinimide are reacted under an atmosphere of nitrogen and the resultant product isolated and purified in the manner described in Example 22B to give 6-bromo-6-flu0ro- 16u-methylcortisone 21-acetate.

B. 6 FLUORO-l6a-METHYL6-DEHYDROCORTISONE 21-ACETATE In the manner described in Example 22C, the 6-br omo- I 6-fluoro-16a-methylcortisone 21-acetate of Example 31A is reacted with 2,4-lutidine and the resultant product isolated and purified to give 6-fiuoro-16ot-methyl-6-dehydrocortisone 2l-acetate.

C. 6FLUORO-16a-METHYL-6-DEHYDROCORTISONE The ZI-acetate of Example 31B is hydrolyzednto the corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6-fluoro-16a-methyl-6-dehydrocortisone.

Alternatively, the compound of this example is prepared by reacting 6-fiuoro-16a-methyl-6-dehydrocortisone 21-acetate, the compound of Example 30B, with chrmium trioxide in acetic acid in the manner described in the alternative procedure of Example 18, and hydrolyzing the resultant 2l-acetate with dilute aqueous sodium hydroxide in the manner of Example 2.

EXAMPLE 32 6-flu0r0-16f3-methyl-6-dehydrohydrocortisone A. G-BROMO-6-FLUORO-16fl-METHYLHYDROCORTISONE ZI-ACETATE The requisite intermediate, 6u-fluoro-lGfl-methylhydrocortisone 21-acetate, is prepared in the manner described in co-pending application Serial No. 770,288 of Nussbaum et al., filed October 29, 1958.

6a-fiuoro-wit-methylhydrocortisone 21-acetate is reacted with bromine in dioxane under nitrogen and the resultant product isolated and purified in the manner describedin Example 253 to give 6-bromo-6-fiuoro-16/3- methylhydrocortisone 21-acetate.

B. G-FLUOROJ6fi-METHYL-6 DEHYDROHYDROCORTI- SONE 2l-ACETATE The 6 bromo 6 fluoro 16B methylhydrocortisone 21-acetate of Example 32A is reacted with 2,4-lutidine and the resultant product isolated and purified 'in the manner described in Example 22C to give 6-fluoro-16,B- methyl-6-dehydrohydrocortisone 21-acetate.

'C. G-FLUORO-lGfl-METHYL-6DEHYDROHYDRO- CORTI SONE The 21-acetate of Example 32 is hydrolyzed to the corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6-tluoro- 16fi-methyl-6-dehydrohydrocortisone.

EXAMPLE 33 6-flu0r0-16,6-methyl-6-a ehydr0c0rtis0ne A. G BROMO-G-FLUORO-l65-YIETHYLCORTISONE '21-ACETATE The requisite intermediate, 6a-fluoro-16,8-methylcortisone 21-acetate, is prepared in the manner described in co-pending application Serial No. 770,288 of Nussbaum et al., filed October 29, 1958.

6a-fluoro-16fl-methylcortisone ZI-acetate is reacted with N-bromosuccinimide under nitrogen and the resultant product isolated and purified in the manner described in Example 22B to give 6-bromo-6-fiuoro-16fi-methylcortisone 21-acetate.

B. G-FLUOROJGB-METHYL-G-DEHYDROCORTISONE 21-ACETATE The 6-b romo-6-fluoro-16 8-methylcortisone 21-acetate of Example 33A and 2,4-lutidine are reacted under a blanket of nitrogen and the resultant product isolated and purified in the manner described in Example 22C to give 6-fluoro-16fl-methyl-6-dehydrocortisone 21-acetate.

C. 6-FLUORO-l6fi-METHYL6DEHYDROCORTISONE The 21-acetate of Example 33B is hydrolyzed to the corresponding 2l-alcolrol by means of dilute sodium hydroxide in the manner of Example 2 to give 6-fiuoro-16flmethyl-6-dehydrocortisone.

Alternatively, 6-fiuoro-16B-methyl-6-dehydrohydrocortisone, the compound of Example 32B, is reacted with chromium trioxide in acetic acid and the resultant product isolated and purified in the manner described in the alternative procedure of Example 18 to give 6-fluoro-16B- methyl--dehydrocortisone 21-acetate, which, in turn, is hydrolyzed to the corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2.

EXAMPLE 34 A. 6-BROMO-6,9a-DIFLUORO 16aMETHYLHYDRO CORTISO'NE 2 l-ACETATE The requisite intermediate, 6,9ot-difluoro-l6a-methylhydrocortisone 21-acetate, is prepared in the manner described in co-pending application Serial No. 770,288 of Nussbaum et al., filed October 29, 1958.

6,90: difiuoro 16cc methylhydrocortisone 2l-acetate is reacted with bromine in dioxane under nitrogen and the resultant product isolated and purified in the manner described in Example 25B to give 6-bromo-6,9a-difiuoro- Mot-methylhydrocortisone 21-acetate.

B. 6,9a-DIFLUORO-16a-METHYL-G-DEHYDROHYDRO- CORTISONE 2l-ACETATE The 6-bromo-6,9zx-difiuoro-4-pregnene of Example 34A is reacted with 2,4-lutidine under nitrogen and the resultant product isolated and purified in the manner de scribed in Example 22C to give 6,9tx-difiu-oro-16a-methyl' 6-dehydrohydrocortisone 21-acetate.

o. 6,9a-DIFLUORO-l6a-METHYL-G-DEHYDROHYDRO- CORTISONE The 2l-acetate of Example 34B is hydrolyzed to the corresponding 2l-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6,9a-difluoro- 16a-methyl-6-dehydrohydro cortisone.

A. 6-BROMO 6,9a-DIFLUORO-16a-METHYLCORTISONE 21-ACETATE The requisite intermediate, 6,9u-difiuoro-l6a-methylcortisone 21-acetate, is prepared in the manner described in co-pending application Serial No. 770,288 of Nussbaum et al., filed October 29, 1958.

6,9a-difluoro-16a-methylcortisone 21-acetate and N- bromosuccinimide are reacted under nitrogen and the resultant product isolated and purified in the manner described in Example 223 to give 6-bromo-6,9u-difluoro- 16ot-methylcortisone 21-acetate.

B. 6,Sa-DIFLUORO-l6a-METHYL-6-DEHYDROCORTISONE 21 ACETATE The 6-bromo-6,9a-difluo-ro-4-pregnene of Example 35A is reacted with 2,4-lutidine and the resultant product isolated and purified in the manner described in Example 22C' to give 6,9a-difluoro-16a-methyl-6-dehydrocortisone 21 -acetate.

'0. 6,9a-DIFLUOROJGwMETHYL-G-DEHYDROCORTISONE The 21-acetate of Example 35B is hydrolyzed to the corresponding 21-alc-ohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6,9u-difl-uoro-16a-methyl-6-dehydroco-rtisone.

Alternatively, 6,9oa-difluf0 16wmethyl-6-dehydrohydrocortisone 21-acetate, the compound of Example 34B, is reacted with chromium trioxide in acetic acid as described in the alternative procedure of Example 18 and the resultant product isolated and purified to give 6,90:- difluoro-16e-methyl-6-dehydrohydrocortisone 21+acetate, which is hydrolyzed to the corresponding 2l-alcohol in the manner described in Example 2 to give 6,9a-difi-uoro- 16a-methyl-6-dehydrocortisone.

EXAMPLE 3 6 A. 6BROMO-6,9ct-DIFLUOROJGB-WIETHYLHYDRO- CORTISONE 2l-ACETATE The requisite intermediate, 6,9u-difluoro-l6fl-methylhydrocortisone 21-acetate, is prepared in the manner described in co-pending application Serial No. 770,288 of Nussbaum et al, filed October 29, 1958.

6,9a-difiuoro-16fl-methylhydocortisone 21-acetate and bromine in dioxane are reacted under an atmosphere of nitrogen and the resultant product isolated and purified in' the manner described in Example 25B to give 6-bromo 6,9a-difluoro-16/3-methylhydrocortisone 21-acetate.

B. 6,9a DIFLUORO-IGB-METHYL-G-DEHYDROHYDRO- CORTISONE 21-ACETATE The 6-bromo-6,9u-difiuoro-4-pregnene of Example 36A is reacted. with 2,4-lutidine under an ato-msphere or nitrogen and the resultant product isolated and purifiedin the manner described in Example 220 to give 6,9Ot-dl fiuoro-16,8-methyl-6-dehydrohydrocortisone ZI-acetate.

C. 6,9a-DIFLUOR0-1Gfi-METHYL-G-DEHYDROCORTISONE The ZI-acetate of Example 36B is hydrolyzed to the corresponding 21-alcohol by means of dilute aqueous.

sodium hydroxide in the manner of Example 2 to give 6,9a-difluoro-16,8-methyl-ddehydrohydocortisone.

EXAMPLE 37 6,9oc-diflu0r0-1 6 B-methyl-6-dehydr0c0rtis0ne A. fi-BROMO-(i,Qa-DIFLUORO-lGfl-METHYLCORTISONE 21ACETATE The requisite intermediate, 6,9a-difluoro-16B-methylcortisone ZI-acetate, is prepared as described in co-pending application Serial No. 770,288 of Nussbaurn et al, filed October 29, 1958.

6,9ot-difluoro-16B-methylcortisone 21-acetate is reacted with N-bromosuccinimide under an atmosphere of nitrogen and the resultant product isolated and purified in the manner described in Example 22B to give 6-bromo- 6,9a-difiuoro-16,8-methylcortisone ZI-acetate.

B. 6,9a-DIFLUORO-1GH-METHYL-B-DEHYDROCORTISONE 21-ACETATE The 6-bromo-6,9a-difluoro-4-pregnene of Example 37A is reacted with 2,4-lutidine under nitrogen and the resultant product isolated and purified in the manner of Example 220 to give 6,9ot-difluoro-l6fi-methyl-6-dehydro cortisone 21-acetate.

C. 6,9a-DIFLUORO16B-\IETHYL-6-DEHYDROCORTISO NE The 21-acetate of Example 37B is hydrolyzed to the corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6,90- difiuoro-l6,8-methl-6-dehydrocortisone.

EXAMPLE 38 6-br0m0-1Ga-methyl-6-dehydr0hydroc0rtisone A. 6,7-DIBROBIO'].Gil-\IETHYLHYDROCORTI'SONE TRIACETATE In the manner described in Example 1, 16u-methyl-6- dehydrohydrocortis-one triacetate, the compound of Example 30F, is brominated and the resultant product isolated and purified to give 6,7-dibromo-IGa-methylhydro cortisone triacetate.

B. S-BROMO-lfia-METHYL-G-DEHYDROHYDR O- CORTISONE TRIACETATE 6,7-dibromo-16a-methylhydrocortisone triacetate, the compound of Example-38A, is reacted with 2,4-lutidine and the resultant product isolated and purified in the manner described in Example 1 to give 6 bromorl6amethyI-S-dehydrohydrocortisone .triace-tate.

C. G-BROMO-lGa-METHYL-G-DEHYDROHYDRO- CORTISONE In the manner described in Example30I, :the triacetate .of Example 38B is hydrolyzed to the corresponding a1- cohol with the aid of a cultureof:Flav0ba cteriwmt dehydrogenans and the resultant product isolated and purified .to give 6-bromo-16a -methyl-6-dehydrohydrocortisone,

EXAMPLE '39,

6-chZora-16oc'methyl-6-dehydrohydrocortisone A. 6,7-DICHLOR0-1Ga-METHYLHYDROCORTISONE TRIACETA'IE i 16a-methyl-6-dehydrohydrocortisone triacetate, the compound of Example 30F, is chlorinatedand the resultant product isolated and purified in the manner .described in Example 5 to give 6,7-dichloro-16u-methylhydrohydrocortisone triacetate.

B. fi-CHLORO-l6a-METHYL-G-DEHYDROHYDRO- CORTISONE TRIACETATE The 6,7-dichloro-4-pregnene,of Example 39A is reacted with 2,4,6-collidine and the resultant product isolated and purified in thetmanner described in Example 5 to give 6-chloro 16a-methyl-6-dehydrohydrocortisone triacetate.

C. 6-CHLOR0-16METHYL-dDEHYDROHYDRd CORTISONE The triacetate of Example 39B is subjected to the action of a culture of Flavobacteriuml dehydrogenans and.

the resultant product; isolated and purified in the manner described in Example 301 togive;6-ch1oro-.16a-methyl-6- dehydrohydrocortisone.

EXAMPLE 40 6-br0mo-16 8-me2hyl-6-dehydr0hydr0cortisone A. IGBWIETHYLHYDROCORTISONE TRIACETATE The requisite intermediate,: 16B-methylhydrocortisone,

is prepared in the manner described in co-pending -;appli-' cation Serial No. 733,843 of Rausser et al, Ifiled'May 8,

1958, now US. Patent No. 3,164,618.

16,8-methy1hydrocortisone is reacted with acetic acid and trifiuoroacetic anhydride' in the manner described in Example 30D and the resultant product isolated and puri-,

fied in the described manner .to. give 16fi methylhydrocortisone triacetate.

B. G-BROMO-IGB-METHYLHYDROCORTISONE TRIACETATE l6fl-methylhydrocortisone triacetate, the compound of Example 40A is reacted Wit-h N-bromosuccinimide in carbon tetrachloride under an atmosphere of nitrogen and the resultant product isolated and purified in the manner described in Example 8A to give 6-bromo-16B-methylhydrocortisone triacetate.

C. 1Gfl-METHYL-G-DEHYDROHYDROCOR'IISONE TRIACTATE 6-bromo-16/3-methylhydrocortisone triacetate, the compound of Example 40B is reacted with 2,4-lutidine and the resultant product isolated and purified in the manner described in Example 8A to give 16B-methyl-6-dehydrohydrocortisone triacetate.

D. 6,7-DIBROMOdGfi-METHYLHYDROCORTISONE TRIACETATE 16,3 methyl 6 dehydrohydrocortisone triacetate, the compound of Example 40C, is brominated and the resultant product isolated and purified in the manner described in Example 1 to give 6,7-dibromo-16p-methylhydrocortisone triacetate.

E. G-BROMOJGE-METHYL-aDEHYDROHYDRo- CORTISONE TRIA-CETATE The 6,7-dibromo-4-pregnene of Example 40D is reacted with 2,4-lutidine and the resultant product isolated and purified in the manner of Example 1 to give 6-bro-mo-16B- methyl-6-dehydrohydrocortisone triacetate.

F. 6-BROMO-1(SB-METHYL-B-DEHYDROHYDRO- CORTISONE The triacetate of Example 40E is hydrolyzed to the corresponding alcohol with the aid of a culture of Flavobacterium dehydrogenans and the resultant product isolated and purified in the manner of Example 301 to give 6-bromo-16fi-methyl-6-de-hydrohydrocortisone.

EXAMPLE 41 6-br0m0-1 6 a-methy l-6-dehydr0hydr0c0rtisone 21 -A ceta te To 1 g. of 6-bromo-16rx-methyl-6-dehyd-rohydrocortisone, the compound of Example 38, there is added 0.5 ml. of acetic anhydride in 2.3 ml. of pyridine. After standing for one hour at room temperature, the mixture is poured into ice and hydrochloric acid. A precipitate results which is filtered and crystallized from aqueous methanol to yield 6-bromo-16a-methyl-6-dehydro-hydrocortisone 2lacetate.

By using propionic anhydride instead of acetic anhyride in the above procedure, there is prepared 6-bromo- 16a methyl 6 dehydrohydrocortisone 21 propionate. Likewise, by substituting any lower alkanoic acid anhydride in the above procedure the corresponding 21-1ower alkanoate is formed.

In a similar fashion, the compounds of Examples 39 and 40 are converted to their 21-esters by reaction of the triol With a lower alkanoic acid anhydride and pyridine.

EXAMPLE 42 6-br0m0-16 -methyl-6-dehydr0c0rtis0ne 21-aceta te 6 bromo-16a-methyl-6-dehydrohydrocortisone 21-acetate, prepared as described in Example 41, is reacted with chromium trioxide in acetic acid in the manner described in the alternative procedure of Example 18 to give 6- bromo-lGot-methyl--dehydrocortisone 21-acetate.

In a similar fashion, 6-chloro-16ot-methyl-6-dehydrohydrocortisone ZI-acetate and 6-brorno-16 3-methyl-6-dehydrohydrocortisone 2l-acetate are oxidized by means of chromium trioxide to the corresponding ll-keto compounds to give 6-chloro-16a-methyl-6-dehydrocortisone 21-acetate and 6-bromo-16 3-methyl--dehydrocortisone 21-acetate.

26 EXAMPLE 43 6,9a-Dibrom0-16a-methyl-6-dehydrohydrocortisone A. ti-BROMO-l6a-METHYL-4,6,9 (11) -PREGNATRIENE- "17d,21-DIOL-3,20DIONE 21-ACETATE Five grams of 6-bromo-16o-methyl-6-dehydrohydrocortisone ZI-acetate, prepared as described in Example 41, is reacted with methanesulfonyl chloride in dimethylformamide and the resultant product isolated and purified in the manner described in Example 28A to give 6-bromoa methyl 4,6,9(11) pregnatriene 17a,21-diol-3,20- dione ZI-acetate.

B. 6,9a-DIBROMO-16a-METHYL-6-DEHYDROHYDRO- CORTISONE 2l-ACETATE To a suspension of 0.3 g. of the 6-bromopregnatriene of Example 43A in 30 ml. of purified dioxane there is added 3 ml. of water containing 0.15 g. of N-bromoacetamide and 1%. ml. of 1.5 N-perchloric acid. The suspension is gently agitated for a period of two hours during which time the mixture becomes homogeneous. A solution of 0.3 g. of sodium sulfite in 3 ml. of water is then added and the reaction mixture is extracted with methylen-e chloride. The organic extracts are combined, washed with Water, dried over magnesium sulfate, filtered and evaporated to a residue which is crystallized from acetonehexane to give 6,9a-dibromo-16ot-methyl-6-dehydrohydrocortisone ill-acetate.

C. 6,9a-DIBROM0-16a-METHYL-G-DEHYDROHYDRO- CORTISONE The Zl-acetate of Example 433 is hydrolyzed to the corresponding 2l-alcohol by means of methanolic perchloric acid in the manner of Example 21D to give 6,9a-dibromo-l6ot-methyl-6-dehydrohydrocortisone.

Similarly, by procedures analogous to those described in this example 6-bromo-16B-methyl-6-dehydrohydrocortisone ZI-acetate, prepared as described in Example 41, is converted to 6-bromo-16,8-methyl-4,6,9( 1 l)-pregnatriene- 17a,2l-diol-3,20-dione 2l-acetate and thence to 6,9a-dibromo methyl-6-dehydrohydrocortisone 21-acetate which is hydrolyzed to the corresponding 21-alcohol to give 6,9a-di'bromo-16,8-methyl-6-dehydrohydrocortisone.

I EXAMPLE 44 6 -br0m O-QOC-Cll 1 010-1 6 :x-methyl -6-d ehydrohydrocortisone A. 6-BROMO-9B,llfl-OXIDO1Ga-METHYL-etfi-PREGNA- DIENE-17a,21-DIOL3,20-DIONE 21-ACETATE To 0.3 g. of 6,9a-di'bromo-16ot-methyl-6-dehydrohydrocortisone 21-acetate, the compound of Example 43B, in 20 ml. of methanol there is added 0.3 g. of potassium acetate. The mixture is refluxed for two hours then concentrated in vacuo to a residue. Water is added to the residue and a solid separates which is filtered and crystallized from methanol-Water to give 6-brom0-9B,1lfioxido 16a-methyl-4,6-pregnadiene-17u,21-diol3,20-dione 21-acetate.

B. -6-BROMO-9aCHLORO-16a-METHYL-6DEHYDRO- HYDROCORTISONE 21-ACETATE The 6-bromo-9,1l-epoxypregnadiene of Example 44A is reacted with a solution of hydrogen chloride in chloroform and the resultant product isolated and purified in the manner described in Example 12B to give 6-bromo- 9a-chlor0-16a-methyl 6 dehydrohydrocortisone 21-acetate.

C. 6BROMO-9a-CHLORO-lGa-DEHYDROHYDRO- 'CORTISONE The 2l-acetate of Example 44B is hydrolyzed to the corresponding 21-alcohol by means of methanolic perchloric acid in the manner of Example 21D to give 6- bromo-9oc-chloro-16a-methyl-6-dehydrohydrocortisone.

In a similar fashion, by using the procedures described in this example 6,9rx-dibromo-16,8-methyl-6-dehydrohydrocortisone 21-acetate, prepared in the manner described 27 in Example 43 is converted to 6-bromo-9,B,llfl-oxido-IQB- methyl-4,6-pregnadiene-l7a,21-diol-3,20-dione 21-acetate and thence to 6-bromo-9a-chloro-l6fl-methyl-6 dehydrohydrocortisone 21-acetate which may be hydrolyzed to. the corresponding 21-alcohol by means of methanolic perchloric acid.

EXAMPLE 45 6,9a-dibrmo-1 6 a-methyl-6-dehydr0c0rtisone 6-bI'OmO-9a-ChlOIO-I6zx methyl 6 dehydrohydrocortisone ZI-a'cetate, the compound of Example 44B, is re; actedwith chromium trioxide in acetic acid in the manner described in the alternative procedure of Example 18 to r give .6 bromo 9a-chloro-16a-methyl-6-dehydrocortisone;

2 1-acetate.

The 21-acetate is converted to the corresponding 21- alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6-bI'OmO-9wChl0l0-16w. methyl-6-dehydrocortisone.

In like manner, 6-bromo-9tx-chloro-l6fl-methyl-6-dehydrohydrocortisone Zl-acetate, prepared as described in Example 44, is oxidized to 6-bromo-9a-chloro-16fi-methyl-6- dehydrocortisone .21-acetate and is then saponified to the corresponding 21-alcohol.

EXAMPLE 47 6-chl0r0-1 6 a-ethyl-6-dehydr0hydroc0rtisone A. G-BROMO-lfia-ETHYLHYDROCORTIS ONE TRIACETATE The requisite intermediate, 16a-ethylhydrocortis0ne 21- acetate, is prepared from hydrocortisone ZI-acetate in the manner described in.co-pending application Serial No. 733,843 of Rausser et al., filed May 8, 1958, now US. Patent No. 3,164,618.

16u-ethylhydrocortisone 21-acetate is reacted With'ace-. tic acid and trifluoroacetic anhydride in the manner described in Example 28D to give 16or-ethylhy-drocortisone triacetate 16ot-ethylhydrocortisone triacetate is reacted with N- bromosuccinimide in carbon tetrachloride under an atmosphere of nitrogen andthe resultant product isolated and purified in the manner described in Example 8A to' give 6-bromo-16a-ethylhydrocortis0ne triacetate.

B. 1Ga-ETHYL-fi-DEHYDROHYDROCORTISONE A TRIACETATE 6-bromo-16a-ethylhydrocortisone triacetate, the compound of Example 47A is reacted with 2,4-lutidine and the resultanttproduct isolated and purified in the manner. described in Example 8A to give 16ot-ethyl-6-dehydrohydrocortisone triacetate.

C. 6,7-DICHLORO-16a.-ETHYLHYDROCORTISONE TRIACETATE 16a-ethyl-6-dehydrohydrocortisone triacetate, the com-.

pound of Example 47B, is chlorinated and the resultant product isolated and purified in the manner described in 23 i Example :5 to give .;6, 7-dichloro-16a-ethylhydrocortisone triacetate.

D. G-CHLORO-16a-ETHYL=6DEHYDROHYDRO- CORTISONE TRIACETATE The ..6,7-dichloro-4-pregnene of Example 470 is reaacted with 2,4,6-collidine and the resultant product isolated and purified in the; manner described in Example 5 to give 6-chl0ro-16a-ethyl-6-dehydrohydrocortisone triacetate.

E. 6-CHLORO-1Ga-ETHYL-G-DEHYDROHYDRO-' 'CORTISONE The triacetate of Example 47D is subjected-tothe, actlon of a culture of Flavobacterium dehydrogenans and the resultant product=isolated and purified in the manner described in Example 301 to give 6-chloro-16a-ethyl-6- dehydrohydrocortisone..

EXAMPLE 48 6-flu0r0-1 6 p-mbutyl-6 -dehydr0c0rtis0ne A. G-BROMO-lGH-D-BUTYDCORTISONE air-ACETATE The requisite intermediate, 16,8-n-butylcortisone 21- acetate, is prepared in themanner; described in' co-pending application Serial'No. 733,843 of Rausser et al., filed May 8,'1958, now ULS. PatentNo. 3,164,618,

16fi-n-butylcortis0ne 21-acetate is reactedw-ith N-bromosuccinimide in the mannerndescribed in Example 8A to give 6-bromo-16/8-n-butylcortisone .21-acetate..

B. lGfi-n-BUTYL-G-DEHYDROCORTISONE 'ZLACETATE The d-bromo-16,3-mbutylc0rtisone 21-acetate of Exam: plei48A is reacted with 2,4-lutidine and the resultant product isolated and purified in the manner described in Example 8A'to give 1GB-n-butyl-6-dehydrocortisone 21-acetate.

C. GFLUJORO-Y-BROMO-i(iii-nBUTYLCORTIS0NE 21-ACETATE 16fl-n-butyl-6-dehydrocortisone ZIPacetate is reacted with hydrogen fluoride and Nebromoacetamide in methylenechlon'de and the resultant product isolated and purified in the manner. described in Example 7 to give 6-fluoro-7- bromo-16,6-n-butylcortisone 21-acetate.

D. e-FLUOR0-1s -n-nutrrn-ennnxnnooonrrsoNn ZI-ACETATE In the manner described in Example 1, the 6-fluoro7- bromo-lfifi-n-butylcortisone ZI-acetateof Example 48C is'reacted with 2,4-lutidine over argon gas and the resultant product isolated andpurified to give 6-fluoro-165-n-.

butyl-6-dehydrocortisone 21-acetate.

E. G-FLUORO-lGfl-n-BUTYL-6-DEHYDROCORTISONE' The 21-acetate of Example, 48D is: hydrolyzed to the corresponding 21,-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6- fiuoro- 1 6,B-n-butyl-G-dehydrocortisone.

EXAMPLE 549 6-fluoro-16a-methyL6-dehydr0prednisolone A. 6-BROMO6-FLUORO-1Ga-METHYLPREDNISOLONE '21-ACETATE The requisite intermediate, 6 8-fiuoro-16B-methylprednisolone 2*1-acetate, is preparedinzthe manner described in co-pendingapplication"Serial No. 7720, 288 of Nuss- 'baum et al., filed October. 29, 1958..

6a fluoro-1Ga-methyIprednisolone 21-acetate is reacted with bromine in dioxane under an atmosphere of'nitrogen and the resultant product isolated. and purified in the manner described in Example 25B -to give 6-bromo-6- fluoro-16a-rnethylprednisolone; 'ZI-acetate.

B.- G-FLUORO-lGGAMETHYL-S-DEHYDROPREDNISOLO-NE ZI-ACETATE In the manner described in Example 220, the 6-bromo- 6--fiuoro-1,4-pregnadienev of Example 49A is reacted with 29 2,4-lutidine under nitrogen and the resultant product isolated and purified in the described manner to give 6-fluoro-l6a-methyl-G-dehydroprednisolone Zl-acetate.

C. B-FLU ORO-l6a-METHYL-6-DEHYDROPREDNISOLONE The 21-acetate of Example 49B is converted to the corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in the manner described in Example 2 to give 6-fluoro-l6a-methyl-6-dehydroprednisolone.

Alternatively, 6-fiuoro-16a-methyl-6-dehydrohydrocortisone, compound of Example 25, is subjected to the action of a culture of Corynebacterium simplex and the resultant product isolated and purified in the manner described in the third procedure of Example to give 6-fluoro-l6amethyl-G-dehydroprednisolone.

EXAMPLE 50 6-flu0r0-1 6 ,B-methyl-6-dehydropredniso lone A. G-BROMO-6-FLUORO-lGfi-METHYLPREDNISOLONE ZI-ACETATE The requisite intermediate, 6a-fluoro-16B-methylprednisolone Zl-acetate, is prepared in the manner described in co-pending application Serial No. 770,288 of Nussbaum et al., filed October 29, 1958.

6a-fluoro-IGB-methylprednisolone 2l-acetate is reacted with bromine in dioxane in the manner described in Example B and the resultant product isolated and purified to give 6-bromo-6-fiuoro 16/3 methylprednisolone 21- acetate.

B. 6-FLUORO1fifl-METHYL-S-DEHYDR OPREDNISOLONE 21-ACETATE The 6-bro-mo-6-fluoropregnadiene of Example 50A is reacted with 2,4-lutidine and the resultant product isolated and purified in the manner described in Example 22C to give 6-fiuoro 165 methyl 6 dehydroprednisolone 21- acetate.

C, 'fi-FLUORO-1(SB-METHYL-6-DEHYDROPREDNISOLONE The ZI-acetate of Example 50B is hydrolyzed to the corresponding 2l-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6-fluoro-16,8-methyl-6-dehydroprednisolone.

Alternatively, 6-fluoro-16B-methyl-6-dehydrohydrocort'isone, the compound of Example 32, is subjected to the action of a culture of Corynebacterium simplex and the resultant product isolated and purified in the manner described in procedure 3 of Example 15 to give 6-fiuoro- 16fi-met hyl-6-dehydroprednisolone.

EXAMPLE 51 6-fluor0- 16a-methyl-6-dehydroprednis0ne A. G-FLUORO-lSa METHYL-G-DEHYDROPREDNISONE 21-A'CETATE 6-fluoro-16u-rnethyl-6-dehydroprednisolone 21-acetate, the compound of Example 48B, is reacted with chromium trioxide and acetic acid and the resultant product isolated and purified in the alternative procedure of Example 18 to give 6-flu=oro 16a methyl-6dehydroprednisone 21- acetate.

B. 6-FLU ORO-l6a-METHYL-6-DEHYDROPREDNISONE -The 2l-acetate of Example 51A is hydrolyzed to the corresponding 21-alco-hol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give Alternatively, by means of the sequence of reactions described in Example 49, Ga flHOIO -16a -methylprednisone 21-acetate is reacted with N- brorn'osuccinimide to obtain the 6-bromo-6-fluoro intermediate which is then reacted with 2,4-lutidine to give 6-fiuoro-l6u-methyl-6- dehydroprednisolone ZI-a'cetate.

30 EXAMPLE 52 6-flu0r0-1 6 5-methyl-6 -dehydr0 prednisone A. 6-FLUORO1(iii-METHYL-G-DEHYDROPREDNISONE ZI-ACETATE 6-fluoro-l6,8-rnethyl-6-dehydroprednisolone 2l-acetate, the compound of Example 50B is reacted with chromium trioxide in acetic acid and the resultant product isolated and purified in the manner described in the alternative procedure of Example 18 to give 6-fiuoro-l6/3-methyl-6- dehydroprednisone 21-acetate.

B. 6-FLUORO-16B-METHYLG-DEHYDROPREDNISONE EXAMPLE 5 3 6 -flu0r0-9oc-br0m0-1 6 a-methy l-6-dehyd r0 prednisolone A. 6 FLUORO-16a-METHYL 1,4,6,9(11)-PREGNATETRA- ENE-17a,2l-DIOL-3,20DIONE 21-ACETATE 6 fluoro-l6a-methyl-6-dehydroprednisolone 21-acetate, the compound of Example 49B, is reacted With methylene sulfonyl chloride in dimethylfor mamide and the resultant product isolated and purified in the manner described in Example 28A to give 6-fluoro-16a-methyl-1,4,6,9(1'1)- pregnatetraene-l7a,2l-diol-3,20-dione 21-acetate.

-C. G-FLUORO-Qa-BROMO-lGa-METHYL-S-DEHYDRO- PREDNISOLONE ZI-ACETATE In the manner described in Example 28B the 6fluoro pregnatetraene of Example 53A is reacted with perchloric acid and N-bromoacetamide, and the resultant product isolated and purified to give 6-fluoro-9a-br0mo-l6u-methyl-6-dehydroprednisolone 21-acetate.

C. (i-FLUORG-9a-BROMO-lGa-METHYL-G-DEHYDRO- PREDNISOLONE The 2'1-acetate of Example 53B is hydrolyzed to the corresponding 21-alcohol with methanolic perchloric acid in the manner of Example 21D to give 6-fiuoro-9a-bromo- 16u-methyl-6-dehydroprednisolone.

EXAMPLE 54 6,9a-diflu0r0-16a-methyl-6-dehydroprednisolone A. G-FLUOROBB,llfi-OXIDO-l6a-METHYL-1,4,6-PREGNA- TRIENE-17a,2l-DIOL-3,20-DIONE ZI-ACE'IATE 6-fiuoro-9a-bromo-l6ot-methyl-6 dehydroprednisolone 2l-acetate, the compound of Example 53B, is reacted With potassium acetate in methanol and the resultant product isolated and purified in the manner described in Example 44A to give 6-fluoro-9/3,1lfi-oxido-l6u-methyl-l,4,6-pregnatriene-l7a,21-diol-3,20-dione ZI-acetate.

B. 6,9a-DIFLUORO l6a-METHYL-6-DEHYDROPREDNIS- OLONE ZI-ACETATE A solution of 0.1 g. of the 6-fiuoro-9/3,1lfl-oxidopregnatriene of Example 54A in 5 ml. of alcohol free chloroform is saturated with anhydrous hydrogen fluoride at 0 C. The mixture is allowed to stand 4 hours at 0 C., then concentrated in vacuo to a residue which is crystallized from acetone-hexane to give 6,9a-difluoro-l6a-methyl-6- dehydroprednisolone 21-acetate.

C. 6,9a-DIFLUORO-16cL-METHYL-6-DEHYDRO- PREDNISOLONE The 21-acetate of Example 54B is hydrolyzed to the corresponding 21-alcohol by means of dilute aqueous 31 sodium hydroxide in the manner of Example 2 to give 6,9a-difiuoro-16a-methyl-6-dehydroprednisolone.

Alternatively, 60:,9or-difit1010 16a methylprednisolone 2l-acetate, prepared as described in co-pending application Serial No. 770,288 of Nussbaum et al., filed October 29, 1958, is reacted With bromine in dioxane in the manner described in Example 25B to give 6-bromo-6,9u-difluoro-- l6a-rnethylprednisolone 21-acetate Which is reacted With- 2,4-lutidine in the manner of Example 220 to give 6,9a-difluoro-l6a-methyl-6 dehydroprednisolone 21-acetate.

A third method of preparing the compound of this example is by subjecting 6,90L-dlfiUOI'O-l6Ct-IIl6thy1-6-dehydrohydrocortisone, the compound of Example 26 to the action of a culture of Corynebacterium simplex in the manner described in the third procedure of Example 15 to give 6,9a-difluoro-16a-methyl-6-dehydroprednisolone.

EXAMPLE 5 5 6-flu0r0-9 t-brm0-1 6 -mezhyl-6 -dehyd ropredn iso lone 6-fluoro-16fl-methyl-6-dehydroprednisolone 2l-ace-tate,

the compound of Example 50B, is reacted with methylenesulfonyl chloride in dimethylfo-rmamide and the resultant product isolated and purified in the manner described in 7 Example 28A to give 6-fiuoro-16fi-methyl-1,4,6,9(l 1)- pregnatetraene-17a,2l-diol-3,20-dione 2l-acetate.

B. G-FLUORG-9a-BROMO-l6BMETHYL-6-DEHYDRO- PREDNISOLONE 21-ACE'1ATE In the manner described in Example 28B, the 6-fiuoropregnatetraene of Example 55A, is reacted with perchloric acid and N-bromoacetamide in t-butyl alcohol and the resultant product isolated and purified to give 6-fiuoro-9abromo-16/3-methyl-6dehydroprednisolone ZI-acetate.

C. 6-FLU ORO-Qu-BROMO-l (SB-METHYL-G-DEHYDRO- PREDNI S OLONE The ZI-acetate of Example 55B is hydrolyzed to the corresponding 2l-alcohol by means of F lavobacterium de-,

B. 6,9a-DIFLUORO-IGH-METHYL-G-DEHYDRO- PREDNISOLONE 21 ACETATE The oxidopregnatriene of Example 56A is reacted with anhydrous hydrogen fluoride in chloroform in the manner 1 described in Example 548 and the resultant product isolated and purified to give 6,9a-difiuoro-16fi-methyl-6-dehydroprednisolone 2l-acetate.

C. 6,9a-DIFLUORO IBB-ME'IHYL-(i-DEHYDRO- PREDNISOLONE The 21-acetate of Example 56B is hydrolyzed to the corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give 6,9ot-difiuoro-16fi-methyl-6-dehydroprednisolone.

EXAMPLE 57 6-flu0ro-9a-chlor0-1 ofl-methyl-6-dehydroprednisolone 21 -acetate 6-fiuoro-9B,l1fi-oxido-16p-methyl 1,4,6 pregnatriene- 17a,21diOl-3,20-di011 21.-acetate, prepared as described intExamplev56A, is reacted with anhydrous hydrogen chloride in chloroform in the manner of Example 12B to give 6-fiuoro-9a-chloro-l6,8-methyl-6-dehydroprednisolone r 21-acetate.

In a similar fashion, 6-fluoro-9fi,11 8-oxido-16a-methyl- 1,4,6-pregnatriene-l7a,2l-diol-3,20-dione 2l-aceta-te, the compound of Example 54A,is converted to 6-fluoro-9achloro-16a-methyl-6-dehydroprednisolone 21,-acetate.

EXAMPLE 5 8 6-flu0ro-9a-ch Zor o-1 6 fi-meth yl-6 dehydroprednisolone 6,9a-difluoro-16u-methyl-6-dehydroprednisolone 2l-acetate, the compound of Example 54B, is reacted with chromium trioxidein acetic acid and the resultant product isolated and purified in the manner described inthe alternative procedure of Example. 18 to give 6,9a-difluoro-16tzmethyl-6-dehydroprednisone 2l-acetate.

In a similar fashion, the ,9OL-bIOI'I1O and 9a-chloro analogs of the compound of this example are prepared from 6-fluor0-9w-bromo-1fiat-methyl 6 dehydroprednisolone Zl-acetate, the compound of Example. 53B; and 6-fluoro-9ot-chloro-16a-methyl-6-dehydroprednisolone 21- acetate, prepared in the manner'described in Example 57.

EXAMPLE -59 6,9oc-diflu010-1 6,8-methyl-6-dehydroprednisone 21 acetate 6,9u-difluoro-l6f3-methyl 6-dehydroprednisolone 21-acetate, the compound of Example 56B,: is reacted with chromium trioxide in acetic acid and the resultant product isolated and purified in the manner described in the alter- I native procedure of Example" 18 to give 6,9CL-diflll0l'0- 16B-methyl-G-dehydroprednisone 2l-acetate.

In a similar fashion, I the 9ot-bromo and 9ot-chloro analogs of the compounds of this example'may be prepared bythe 'chromic acid oxidation of 6-fiuoro-9abromo-16fl-methyl-6-dehydroprednisolone 21-acetate, the compound of Example 55B; and 6-fiuoro-v9a-chloro-16pmethyl-6-dehydroprednisolone '2l-acetate, prepared as described in Example 5 7.

EXAMPLE 6O A. 6-BROMO6-FLUORO-16B-n-BUTYLPREDNISONE ZI-ACETATE The requisite intermediate, 6a-fluoro-16/3-n-butylprednisone 21-acetate, is prepared in the manner described in co-p'ending application Serial No. 770,288 of Nussbaum et al., filed October 29, 8

60a fluoro 166 n butylp'rednisone V 21 acetate is reacted with N-bromo-suecinimide': under an atmosphereof nitrogen and the resultant productisolated and purified in themanner described in Example 22B to give 6-bromo-6-fluoro-16B-n-butyl prednisone 21-acetate.

B. 6FLUORO-lGfi-n-BUTYL-6DEHYDROPREDNISONE ZI-ACETATE The 6 bromo 6 fluoro 16,6 n butylprednisone 21-acetate of Example 60A is reacted with.2,4-lutidine and the resultant product isolated and purified in the manner described in Example 220 to -give6-fiuoro-16,B-

n-butyl-6-dehydroprednisone 21-acetone.

C. G-FLUORO-l6fl-n-BUTYL-6-DEHYDROPREDNISONE The ZI-acetate of-Example 60B is hydrolyzedto the corresponding 21-alcoho1 by means ,of dilute aqueous sodiumhydroxide in the manner described in Example 2 to give 6-fluoro-16,8-n-butyl-6-dehydroprednisone...

EXAMPLE 61 i 6-brom0-16u-methyl-6-dehydr0prednisolone A. 16METHYLPREDNISOLONE ,VTRIACETATE The requisite intermediate, 16a-methyl'predniso1one 21- acetate, is prepared in the manner describedinicoapendq ing application Serial No. 733,843 of Rausser et a1., filed May 8, 1958, now US. Patent No. 3,164,618.

16a-methylprednisolone 2l-acetate is reacted with acetic acid and trifluoroacetic anhydride in the manner of Example 30D to give 16u-methylprednis0lone triacetate.

B. 6-BROM0-16a.-METHYLPREDNISOLONE TRIACEIATE The triacetate' of Example 61A is reacted with N- bromosuccinimide in carbon tetrachloride under an atmosphere of nitrogen and the resultant product isolated and purified in the manner described in Example 8A to give 6-bromo-16a-methylprednisolone triacetate.

C. 1Ga-METHYL-G-DEHYDROPREDNI'SOLONE TRIACETATE The 6-bromo \compound of Example 61B is reacted with 2,4-lutidine and the resultant pnoduct isolated and purified in the manner described in Example 8A to give 16a-methyl-6-dehydroprednisolone triacetate.

D. 6,7-DIBROM-16a-ME'IHYLPREDNISOLONE TRIACETA'IE l6a-methyl-6-dehydroprednisolone triacetate, the compound of Example 61C is brominated in the manner of Example 1 to give 6,7-dibromo-16a-methylprednisolone triacetate.

E. 6-BROMO-16a-METHYL-G-DEHYDROPREDNISOLONE TRIACETATE In the manner described in Example 1, the 6,7-dibromide of Example 61D is reacted with 2,4-lutidine and the resultant product isolated and purified to give 6- bromo-l6a-methyl-G-dehydroprednisolone triacetate.

F. G-BROMO-l6a-METHYL-G-DEHYDROPREDNI'S OLONE EXAMPLE 62 6,9a-dibr0m0-16ot-methyl-6-dehydroprednisol0ne A. 6-BROM0-1Ga-METHYL-S-DEHYDROPREDNISOLONE 21-ACETATE 6-bromo-l6a-methyl-6-dehydroprednisolone, prepared as described in Example 61, is reacted with acetic anhydride in pyridine in the manner described in Example 41 to give 6bromo-16u-methyl-6-dehydropreduisolone 21- acetate.

B. 6-BROMO-16a-METHYL-L4,6,9(11)-PREGNATETRA- ENE-'17a,'21-DIOL-3,20-DIONE 21-ACETATE In the manner described in Example 28A, 6-bromo-16umethyl-6-dehydroprednisolone 21-acetate, the compound of Example 62A, is reacted with methylenesulfonylchloride in dimethylformamide and the resultant product isolated and purified to give 6-bromo-16amethyl-1,4,6, 9( 11)4pregnatetraene-17u,21-diol-3,20-dione 21-acetate.

C. 6,Qa-DIBROMO-16a-METHYL-G-DEHYDROPREDNIS- OLONE 21-ACETATE The 6-bromopregnatetraene of Example 62B is reacted with N-brotmo-acetamide and penchloric acid and the resultant product isolated and purified in the manner described in Example 43B to give 6,9a-dibr0mo-l6a-methyl- 6-dehydroprednisolone ZI-acetate.

D. 6,9wDIBROMOlGa-METHYL-G-DEHYDRO- PREDNISOLONE The ZI-acetate of Example 62C is hydrolyzed to the corresponding 21-alcohol by means of methanolic perchloric acid in the manner of Example 21D to give 6,9adibromo-l6wmethyl-6-dehydroprednisolone.

Alternatively, the compound of this example may be prepared by the following procedures, E, F, G, H, I, :and J.

E. 9B,11flOXIDO-16a METHYL-l,4-PREGNADIENE-17a,21-

DIOL3,20-DIONE 21-ACETATE The requisite intermediate, 9u-bromo-l6a-methylprednisolone 21-aoetate, is prepared in the manner described in co-pending application Serial No. 733,843 of Rausser et al., filed May 8, 1958, now US. Patent No. 3,164,618.

9a-bromo-16amethylprednisolone 21-acetate is reacted with potassium acetate in methanol in the manner described in Example 44A. The resultant product is isolated and purified in the described manner to give 9,8, 11,8-oxido-l6a-methyl-l,4-pregnadiene-17a,21 diol-3,20- dione 2l-acetate.

F. G-BROMO-QB,1lfi-OXIDO-l6u-METHYL-1,4-PREGNA- DIENE-17a,2l-DIOL-3,'20-DIONE ZI-ACETATE In the manner described in Example 8A, the 95,11,8- oxido of Example 62E is reacted with N-brornosuccinimide under an atmosphere of nitrogen and the resultant product isolated and purified to give 6-bromo-9B,11 3- oxido-l6a-methyl-1,4 pregnadiene-17u,2l-diol 3,20 dione 21-acetate.

G. 9B,11B-OXIDO lGa-METHYLd,4,6-PREGNATRIENE- 17a,21-DIOL-3,20-DIONE 21-A-CETATE In the manner described in Example 8A, the 6-bromo- 9,8,1 lfl-oxido-pregnadiene of Example 62F is reacted with 2,4-lutidine and the resultant product isolated and purified to give 93,1lfl-oxido-l6a-methyl-1,4,6-pregnatriene-l7a, 21-diol-3,20-dione 21-acetate.

H. 6,7-DIBROMO-9/3,1lfl-OXIDO-l6aMETHYL-1,4-PREGNA- DIENE-l'la,2lDIOL 3,20DIONE 21-A CETATE The 95,11fl-oxidopre-gnatriene of Example 62G is brominated in the manner described in Example 1 to give 6,7-dibromo-9B,l lfi-oxido-l6a-methyl 1,4 p-regnadienel7a,21-diol-3,20-dione 21-acetate.

The 6,7-dibromo of Example 62H is reacted with 2,4- lutidine and the resultant product isolated and purified in the manner of Example 1 to give 6-bromo-9,8,11 8- oxido-16a-methy1-1,4,6-pregnatriene 1704,21 diol 3,20- dione 21-acetate.

J. 6,9aDIBROMO-l6a-METHYL-G-DEHYDROPREDNIS- OLONE ZI-ACETATE The 6-bromo-9B,1lfi-oxidopregnatriene of Example 621 is dissolved in carbon tetrachloride and reacted with hydrobromic acid in acetic acid in the manner of Example 11C. The resultant product is isolated and purified in the described manner to give 6,9a-dibIOmO-16a-IIl6thYl- 6-dehydroprednisolone 2l-acetate.

EXAMPLE 63 6-br0m0-9a-flu r0-1 6 a-methy l-6-dehydr0prednis0l0ne 21 -acetate 6-bromo-9fl,1lfi-oxido-16amethyl-l,4,6 pregnatriene- 17a,21-diOl-3,20-di011, the compound of Example 62I, is reacted with anhydrous hydrogen fluoride in chloroform and the resultant product isolated and purified in the manner described in Example 54B to give 6-bromo-9afluoro-16a-methyl-6-dehydroprednisolone 2l-acetate.

EXAMPLE 64 6-chl0r0-1 6a-methyl-6-dehydroprednis0lone A. a,Ga-OXIDOd6a METHYL-1-PREGNENE-1lB,17a,21-

, TRIOL-B,20-DIONE ZLACETATE The requisite intermediate, l6a-methyl1,5-pregnadiene-l118,17 ;1-triol-3,20-dione ZI-acetate, is prepared mannerdescribed in Example 238 to give 6OL-Cl1lO1O-16Dtmethylprednisolone 2l-acetate.

C. 6BROMO-6'CHLORO-1(Sc-METHYLPREDNISOLONE 21-ACETATE The 6-chloro-16a-methylprednisolone 21-acetate of Example 64B is reacted with bromine in dioxane and the resultant product isolated and purified in themanner describedin Example 25B to give 6-hromo-6-chloro-16mmethylprednisolone 2l-acetate.

D. G-CHLORO-l6a-METHYL-6DEHYDROPREDNISOLONE 21-ACETATE In a manner similar to that described in Example 22C,

6-bromo-6-chloro-16(x-methyl-6 dehydroprednisolone 21- t acetate, of Example 640, is reacted with 2,4-lutidine and the resultant product isolated and purified to give 6-chloro- 16a-methyl-6-dehydroprednisolone 21-acetate.

E. 6CHLORO-16a-METHYL-fi-DEHYDROPREDNISOLONE The 21-acetate of Example 64D is hydrolyzed to the corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in the manner of Example 2 to give ,6- chloro-l6oc-rnethyl-6-dehydroprednisolone.

EXAMPLE 65 6,9u-dibr0'm0-16a-methyl-6-dehydroprednis0ne '21 acetate 6,9u.-dibromo-16a-methyl 6 dehydroprednisolone 21-' acetate, the compound of Example 62C, is reacted with chromium trioxide in acetic acid and the resultant product.

isolated and purified in the manner described in the alternative procedure of Example'18 to give -6,9a-dibr,oinot 16a-rnethyl-6-dehydroprednisone ZI-acetate.

In like manner, the l6amethyl-ll-hydroxy compounds of Examples 61, 63 and 64 are convertedto the corre-i sponding ll-keto compound-s when oxidized by means of;

chromium trioxide in acetic acid.

EXAMPLE 66 6,9u-dibrom o-l 6 fl-methy l-6-dehydroprednisol one 21-acetate 6,9a-dib-romo-l6/3-methyl-6-dehydrohydrocortisone 21- acetate, prepared as described in Example 43C, is subjected to an action of a culture of Corynebacteriumsimplex and the resultant product isolated and purified in the: manner similar to that described in the third procedure of Example 15 to give 6,9u-dibromo-l6fl-methyl-6-dehydroprednisolone'21-acetate,

EXAMPLE 67 6-br0mo-9u-flu0r0J 6 p-methy l-6-dehydroprednisolone 21 acetate 6-bromo-9a-fluoro-16B-methyl 6 dehydrohydrocortisone 2l-acetate, prepared as described in Example 9, is subjected to the action of a culture of Corynebacterium 6-dehydroprednisone..

36" simplex and the resultant product'isolated and purified in the manner of the third procedure of Example 15, to give 6-bromo-9oz-fluoro-16fl methyl 6 dehydroprednisolone 2l-acetate.

EXAMPLE 68 6-br0m0-9oc-flu0r0-1 6 fl-methy l-6-dehydroprednisane 21 -wcetate 6-bromo-9u-fiuoro-l6/3-rnethyl-6 dehydroprednisolone ZI-acetate, the compound of Example 67, is reacted with chromium trioxide in acetic acid and the resultant product isolated and purified in the manner described in the alternative procedure of Example: 18 to give 6-bromo-9ot fiuoro-l 6,8-methyl-6-dehydroprednisone .21-acetate.

In;a similar, manner, the 9o'a-bromo analog'of the compound of this example is. prepared from 6,9a-dibromo- 16,8-methyl 6-dehydroprednisolone 21,-acetate,; the compoundof Example 66 when reacted with chromium trioxide in' acetic acid.

The 21-acetate of Examplet68is hydrolyzed to the corresponding ZI-alcohol in chloroform methanol by means ofdilute aqueousssodium ,hydroxidein the manner described in Example 2 to give6-bromo-9wfluoro-16fl methyl-6-dehydroprednisone.

In a similar manner; 6,-9a-dibromo-16fl-methyl-6-dehydroprednisone ZI-aoetate, preparedas described in Example 68, fishydrolyzed to give 6,9wdibromo-16/3-methyl- EXAMPLE 70 6,9w-diflu'0r0-16u-methyl-d-dehydropredn isone 6,9a-ditluoro-16a-methyl-6-dehydroprednisone 21-acetate, prepared as described vinExample58, is hydrolyzed to the cor-responding 21-alco'hol by'means of dilute aqueous sodium hydroxide in methanol-chloroform'in the manner described in Example 2 to give 6,9a-difluoro-lfioe-methyl 6dehydrop-rednisone.

In a similar fashion, -6-fluo-ro-9u-bromo-16a-methyl-6- de'hydroprednisone 21-acetate and 6-fiuo-ro-9o-chloro-16umethyl-6-dehydroprednisone 21-acetate, prepared accordingto the procedure of Example-58, are hydrolyzed to 7 their corresponding 214110011015,"'6fll.IOITO-90c-1bl'OmO-160tmethyl-6-dehydroprednisone, respectively.

EXAMPLE ,71

6,9m-difluoro-l 6 fi-methyl-6-dehydroprednisone -6,-9a-di'fluoro-16 8-methyl-6-dehydroprednisone 21-acetate, the compound of Example 59,-is hydrolyzed to the corresponding ZI-alcohol by means of dilute aqueous sodium hydroxide in methanol-chloroform in the manner described in Example 2 to give 6,9a-diflu0ro-l6B-methyl- 6-dehydroprednisone.

In a similar fashion, 6-fluoro-9u-bromo-16fi-methyl-6- dehydroprednisone 21-acetate and 6-fluoro-9a-chloro-16B1 'methyl-6-dehydroprednisone ZL-acetate, prepared in the manner of Example 59, :is hydrolyzed to their corresponding ZL-alcohols, 6-fluoro-9a-bromo-16,3-methyl-6-dehydroprednisone and i6-fluoro-9a-chloro-16fi-methyl-6-dehydroprednisone, respectively EXAMPLE 72 6-br0m0-16bt-methyl-6-dehydroprednisone 6-brorno-16a-methyl-6-dehydroprednisolone ZI-acetate,

preparedas described in Example-62A, is reacted with chromium trioxide in acetic acidrand the; resultant prod not isolated and purified in the manner described, in the alternative procedure of Example 118 to give 6-bromo-16amethyl-6-dehydroprednisone ZI-acetate.

The Ill-acetate prepared above is hydrolyzed to the corresponding -2l-alc0hol byimeans of dilute? aqueous sodium,

hydroxide in the manner described in Example 2 to give 6- hromo-l 6ot-methyl-6-dehydroprednisone.

EXAMPLE 73 6-flu0r0-9a-br0m0-6-dehydroprednisone 6-fluoro-9a-bronio-6 hydroprednisolone 214acetat-e, the compound of Example 28B, is reacted with chromium trioxide :in acetic acid in the manner described in the alternative procedure of Example 18 to give 6fluoro-9o-b romo- G-dehydroprednisone 21-acetate.

The ZI-acetate prepared above is hydrolyzed to the corresponding 21-a-lcohol by means of methanolic perchloric acid in the manner of Example 21D to give 6-fluoro-9abromo-d-dehydroprednisone.

EXAMPLE 74 6,9u-dibrm0-6-dehydroprednisone 6,9a-dibromo 6 dehydroprednisolone 21-acetate, the compound of Example 21C, is reacted With chromium trioxide in acetic acid and the resultant product isolated and purified in the manner described in the alternative procedure of Example 18 to give 6,9a-dibromo-6-dehydroprednisone 21-acetate.

The ZI-acetate prepared above is hydrolyzed to the corresponding 21alcohol 'by means of methanolic perchloric acid in the manner of Example 21D to give 6,9u-dibromo- 6-dehydroprednisone.

EXAMPLE 75 6-br0m0-9a-fluoro-ti-de-hydrocortisone 6-bromo-9a-fluoro-d-dehydrohydrocortisone 2l-acetate, the compound of Example 9, is reacted with chromium trioxide in acetic acid and the resultant product isolated and purified in the manner described in the alternative procedure of Example 18 to give 6b-I'OHIO-9OL-fiHOTO-6-d6- hydrocortisone 21-acetate.

The 2l-acetate prepared above is hydrolyzed to the corresponding 21-alcohol by means of dilute aqueous sodium hydroxide in the manner described in Example 2 to give 6-bromo-9a-fluoro-6-dehyd-rocortisone.

EXAMPLE 76 6-fluoro-6-dehydrohydrocortisone A. Ga-FLUOROHYDROCORTISONE 21-ACETATE 6u-tfluorohydrocortisone is reacted with acetic anhydride in pyridine and the resultant product isolated and purified in the manner described in Example 22A to give 6ot-fluorohydrocortisone 21-acetate.

B. G-BROMO-G-FLUOROHYDROCORTISONE ZI-ACETATE 60t-fl1101'OhYdl'OCOI'tiSOI1e ZI-acetate, the compound of Example 76A, is reacted with bromine in dioxane under nitrogen in the manner of Example 25B. The resultant product is isolated and purified in the described manner to give 6-bromo-6fluorohydrocortisone Zl-acetate.

C. G FLUORO-G-DEHYDROHYDROCORTISON E 21-ACETATE The 6-bromo-6-fluorohydrocortisone 21-acetate of Example 76B is reacted with 2,4-lutidine under nitrogen and the result-ant product isolated and purified in the manner described in Example 220 to give 6-fluoro-6-dehydrohydrocortisone ZI- acetate.

D. G-FLUORO G-DEHYDROHYDROCORTISONE The 21-acetate of Example 76C is hydrolyzed to the corresponding 21-a1cohol with 1:2 chloroform-methanol 'with dilute aqueous sodium hydroxide in the manner described in Example 2 to give 6-fiuoro-6-dehydrohydrocortisone.

38 EXAMPLE 77 6-fluor0-9a-brom0-6-dehydrohydrocortisone The 2l-acetate of Example 77B is hydrolyzed to the corresponding 2l-alcohol with methanolic perchloric acid in the manner of Example 21D to give 6-fluoro-9a-bromo 6-dehydro'hydrocortisone.

EXAMPLE 78 6-flu0r0-9a-chl0r0-6-dehydrohydrocortisone A. 6FLUORO-9B,11BOXIDO-4,6-PREGNADIENE17a,21- DIOL-3,20DIONE 'ZI-ACETATE 6-fluoro-9a-bromo-6-dehydrohydrocortisone ZI-acetate, the compound of Example 77A, is reacted with potassium acetate in methanol and the resultant product isolated and purified in the manner described in Example 44A to give 6 fluoro 95,11fi-oXido-4,6-pregnadiene-17a,21-diol-3,20- dione 2l-acetate.

B. 6-BROMO9a-CHLORO-6-DEHYDROHYDROCORTISONE 21-ACETATE The 6-fluoro-9,ll-epoxypregnadiene of Example 78A is reacted with a solution of hydrogen chloride in chloroform and the resultant product isolated and purified in the manner described in Example 12B to give 6-bromo- 9wchloro-6-dehydrohydrocortisone 21-acetate.

C. G-FLUORO-Qa-CHLORO-G-DEHYDROHYDROCOR- TISONE The 21-acetate of Example 78B is hydrolyzed to the corresponding 21-alcohol by means of methanolic perchloric acid in the manner of Example 21D to give 6- fluoro-9a-chloro-6-dehydrohydrocortisone.

6-fluoro-9ot-bromo-6-dehydrohydrocortisone 21 acetate, the compound of Example 77B, is reacted with chromium trioxide in acetic acid in the manner described in the alternative procedure of Example 18. The resultant product is isolated and purified in the described manner to give 6-fluoro-9a-bromo-6-dehydrocortisone 21-acetate.

The 2l-acetate prepared above is hydrolyzed to the corresponding 21-a1cohol by means of a culture of Flavobacterium dehydrogenans in the manner described in Example 301 to give 6-fluoro-9tx-bromo-6-dehydrocortisone.

EXAMPLE 80 6-fluoro-9a-bromo-6-dehydr0c0rtis0ne 6-fluor0-9a-chloro-6-dehydrohydrocortisone 21-acetate, the compound of Example 78B is reacted with chromium trioxide in acetic acid in the manner described in the alternative procedure of Example 18. The resultant product is isolated and purified in the described manner to give 6-fluoro-9u-chloro-6-dehydrocortisone 21acetate. The 2l-acetate prepared above is hydrolyzed to the corresponding 2l-alcohol by means of a culture of geno-1,4-pregnadienes of the following formula and the,

1,2-dihydro analogs thereof:

OHIOR whereinX is a member of the group consisting of H21 and halogen of atomic weight less than 126;.Y is a member of the group consisting of O and (H, liOH'); Z and Z are halogens of atomic weight less than 126; A is a member of the group consisting of H. andlowe-r alkyl; and R is a member of the group consisting of1 hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive- 2. A compound of claim. 1 wherein X is H, Y is (H, {30H}, Z in bromo, Z isfluoro, R is lower alkanoyl and A is a member of the groupconsisting of H and: methyl.

3. A compound of claim 1, wherein X is H, Yis 0, Z is bromo, Z" is fluoro, R is lower alkanoyl and Ais a member-of the group consisting of H and methyl.

4. A compound of claim 1, wherein X is'F, Y is (H, 'BOH), Z is bromo, Z is fluoro, R is'lower alkanoyl and A is a member of the group consisting of H and methyl.

5. A l-dehydro compound of claim 1 wherein Xis H, Y is (H, ,BOH), Z is bromo, Z is chloro, A is H and R is .acetyl, said compound being 6-chloro-6-bromo-. prednisolone 2l-acetate.

6. A l-dehydro compoundof claim 1 wherein X'is H, Y is (H, BOH), Z is bromo,,Z' is chloro, A is cc-methyl and R is acetyl, said compound being 6-chloro-6-bromo- 16a-methyl-prednisolone21-acetate.

7. A l-dehydro compound of claim 1 wherein X is F, Y is (H, 50H), Z is bromo, Z is fluoro, A is H and R is acetyl, said compound being 6-fluoro-6-bromoprednisolone acetate.

8. A 1,2-dihydro compound of claim 1 wherein X is F, Y is (H, 50H), Z is bromo, Z is fluoro, A is methyl and R is acetyl, said compound being 6-fluoro-6-bromo1 9a-fluoro-l6-methyl-prednisolone ZI-acetate.

9. A compound of the group consisting of 6-bromo- 4,6-pregnadienes of the following formula, and the 1- dehydro analogsthereof wherein X is a member of thegroup consisting of H and halogen, Y is a member of the group consisting of O and (H, SOH )',=A is a member. of the group consisting of H and methyl; andR is a member of the 1 group COD:

' sisting of H-. and 'loweralkanoyl.

10. A compoundof. claim 9=wherein X is fluoro, Y is (H, SOH), A is Hand R iisnlower :alkanoy-l;

11. A 'compound of claim 9 wherein X .isfluoro, -Y

is (H, fiOH), A is methyl and .R is loweralkanoyl.

12. A compound Of'C1almF9 wherein X isQH, Y is- (IL 30H) A is and R 'isslower. alkanoyl.

13. In the process of preparing compounds of the group consisting of pregnatrienes of the following formula:

wherein XisQa member of the group ,consisting of H and halogen of atomic ,weightiless than '126; Y is a member of the group consistingof O and .(H, 50R) Z is a halogenof atomic weight less than '126; Ais a member of the group. consisting of H; and lower alkyl; and R518 a member of the. group consisting of H and lower alkanoyl; and the 1,2-dihydro analogs thereof; the steps-which comprise halogenating a compound of the formulas.

wherein A,:X, Y; andv R are aswabove defined, and-the 1,2-dihydro analogs thereof whereby there is formeda 6,7-dihalogeno intermediate, and dehydrohalogenating said intermediate by meansof an organic base.

14. The process of claim13 wherein 6-dehydrocortisone2 21acetate is brominated to yieldthe intermediate 6,7-dibromocortisone ZI-acetate and said intermediate is dehydrobrominated by'means of 2,4- 1utidine, and the.

resulting 6-bromo-6-dehydrocortisone 21i-acetate .thereby formed is isolated.

15.? The, process of claim '13 wherein 6-dehydrohydrocortisone ZI-acetate is brominated to give the intermediate 6,7-dibromohydrocortisone 21t-acetate, and said iintermediate is dehydrobrominated by means of dimethylformamide, and the 6-bromo@6-dehydrohydrocortisone; thereby formed is isolated.

16.1 The. process of claim .13,wherein 9a'-fluoro-6-dehydrohydrocortisone ZI-acetate is brominated by means of hydrogen bromide and bromine to give the intermediv ate, 6,7-dibromo-6-dehydrohydrocortisone ZI-acetate, and saidintermediate is dehydrobrominated by means of 1utidineand the =6-bromo-9a-fluoro-6-dehydrohydrocortisone- 21Aacetate thereby formed is isolated. t i

17. The process of-preparing compounds of the grou 

1. COMPOUNDS OF THE GROUP CONSISTING OF 6,6-DIHALOGENO-1,4-PREGNADIENES OF THE FOLLOWING FORMULA AND THE 1,2-DIHYDRO ANALOGS THEREOF: 